Clinical Trial Results:
90-Yttrium-labelled anti-CD66 monoclonal antibody as part of a reduced intensity conditioning regimen prior to allogeneic haematopoietic stem cell transplantation: an open label, dose escalating phase I study in children with relapsed/refractory leukaemia
|
Summary
|
|
EudraCT number |
2013-000015-24 |
Trial protocol |
GB |
Global end of trial date |
14 May 2020
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
17 Apr 2021
|
First version publication date |
17 Apr 2021
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
07MI05
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT04082286 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Great Ormond Street Hospital for Children NHS Foundation Trust
|
||
Sponsor organisation address |
30 Guilford Street, London, United Kingdom,
|
||
Public contact |
Dr. Robert Chiesa, Dr. Robert Chiesa, 44 2079052863, CTIMP.Safety@gosh.nhs.uk
|
||
Scientific contact |
Dr. Robert Chiesa, Great Ormond Street Hospital for Children NHS Foundation Trust, robert.chiesa@gosh.nhs.uk
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
11 Mar 2021
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
14 May 2020
|
||
Was the trial ended prematurely? |
Yes
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To determine whether a radiolabelled antibody that tergets the bone marrow (the anti-CD66) can be administered safely to children as part of the preparative treatment prior to haematopoietic stem cell transplantation.
To evaluate the safety (and maximum tolerated dose) and feasibility of targeted radiotherapy delivered by 90-Yttrium-labelled anti-CD66 monoclonal antibody within a reduced intensity conditioning regimen in children with relapsed/refractory leukaemia undergoing allogeneic haematopoietic stem cell transplantation.
|
||
Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, the general principles indicated in the Declaration of Helsinki, and all applicable regulatory requirements. Prior to initiation at each study center, the study protocol was reviewed by an Independent Ethics Committee (IEC). All subjects were to provide written informed consent prior to entering the study and before initiation of any study-related procedure (including administration of investigational product). The investigator was responsible for explaining the benefits and risks of participation in the study to each subject or the subject’s legally acceptable representative and for obtaining written informed consent.
|
||
Background therapy |
Patients would receive a reduced intensity conditioning regimen consisting on Fludarabine (150 mg/sqm), Treosulfan (30-42 g/sqm), Thiotepa (10 mg/kg) +/- Alemtuzumab or ATG will be administered after the infusion of 90Y-labelled anti-CD66 monoclonal antibody, starting from day – 8 prior to transplant. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
26 May 2016
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
United Kingdom: 9
|
||
Worldwide total number of subjects |
9
|
||
EEA total number of subjects |
0
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
5
|
||
Adolescents (12-17 years) |
4
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||
|
Recruitment
|
|||||||
Recruitment details |
This study was conducted at 2 sites in the UK (GOSH and UCLH) between 26-May-2016 (First Patient enrolment) and 15-Aug-2019 (Last Patient enrolment). | ||||||
|
Pre-assignment
|
|||||||
Screening details |
14 subjects were screened and consented for this study, but 5 patients failed the screeneing phase. Nine patients were eventually recruited and treated with radio-immunotherapy | ||||||
|
Period 1
|
|||||||
Period 1 title |
Baseline & Overall Study Period (overall period)
|
||||||
Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
|
||||||
Blinding used |
Not blinded | ||||||
Blinding implementation details |
not applicable
|
||||||
|
Arms
|
|||||||
|
Arm title
|
Infusion of Yttrium-90 labelled monoclonal anti-CD66 antibody | ||||||
Arm description |
Patients enrolled into this study received a single dose of Yttrium-90 labelled anti-CD66 antibody as part of a reduced toxicity conditioning regimen, prior to allogeneic haematopoietic stem cell transplant | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Indium-111-labelled anti CD66 monoclonal antibody
|
||||||
Investigational medicinal product code |
In111i
|
||||||
Other name |
|||||||
Pharmaceutical forms |
Concentrate for solution for injection
|
||||||
Routes of administration |
Intravenous use
|
||||||
Dosage and administration details |
100 MBq/sqm, given as a single dose iv over 15-30 minutes
|
||||||
Investigational medicinal product name |
Yttrium-90 labelled anti CD66 monoclonal antibody
|
||||||
Investigational medicinal product code |
Y90
|
||||||
Other name |
|||||||
Pharmaceutical forms |
Injection
|
||||||
Routes of administration |
Intravenous use
|
||||||
Dosage and administration details |
0.5-3 mg of antibody protein (with increasing doses of Yttrium90, according to protocol) infused iv as a single dose
|
||||||
|
|||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Baseline & Overall Study Period
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Children with relapsed/refractory leukaemia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Infusion of Yttrium-90 labelled monoclonal anti-CD66 antibody
|
||
Reporting group description |
Patients enrolled into this study received a single dose of Yttrium-90 labelled anti-CD66 antibody as part of a reduced toxicity conditioning regimen, prior to allogeneic haematopoietic stem cell transplant | ||
|
|||||||||
End point title |
Safety endpoint: assessment of dose limiting toxicity [1] | ||||||||
End point description |
Dose-limiting toxicity (DLT) was defined as follows, using the National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 4.0) :
a) graft failure: neutrophils < 0.5 x 109/L by day + 45 post transplant (unless clearly due to concomitant infections, other medications or poor stem cell dose/viability);
b) Hepatic/gastrointestinal toxicity (excluding oral mucositis) by day +30 post transplant: ≥ grade 3, excluding causes such as concomitant drugs, infections or GvHD;
c) Gastrointestinal toxicity (oral mucositis) by day +30 post transplant: > grade 3, excluding causes such as concomitant drugs, infections or GvHD;
d) Neurological toxicity by day +30 post transplant: ≥ grade 3, excluding causes such asconcomitant drugs or infections;
e) Pulmonary toxicity by day +30 post transplant: ≥ grade 3, excluding infectious causes, peri-engraftment syndrome or concomitant drugs;
f) Cutaneous toxicity by day +30 post transplant: ≥ grade 3, excluding concomitant drug reactions, infe
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Assessment of dose limiting toxicity (DLT) within 30 days post-stem cell transplant
|
||||||||
| 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: Children received increasing doses of targeted radio-immunotherapy, with a max infused activity of 47 MBq/kg and a max absorbed dose to the bone marrow= 45 Gy. As the antibody used in this trial expired, the study ended prematurely and we couldn't escalate the dose up to 55 MBq/kg. Nevertheless children in the last cohort received a high dose of radiation to the bone marrow and RIT was extremely well tolerated by 9/9 children. None experienced a Dose Limiting Toxicity. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Disease response after 90Yttrium-labelled anti-CD66 monoclonal antibody | ||||||||
End point description |
To assess disease response after RIT and stem cell transplant.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Disease response at 1 year post-stem cell transplant
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Timing of myeloid and platelet recovery after allogeneic haematopoietic stem cell transplantation | ||||||||||||
End point description |
Timing of myeloid and platelet recovery after allogeneic haematopoietic stem cell transplantation
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Timing of myeloid and platelet recovery within 2 months post-stem cell transplantation
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||
End point title |
Donor engraftment rate and quality of chimerism after allogeneic haematopoietic stem cell transplant | ||||||||||
End point description |
Analysis of donor engrfatment after BMT.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Chimerism d+30 post transplant
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||
End point title |
Biodistribution of Indium-111, after imaging with gamma camera / SPECT-CT scans and blood samples | ||||||||||
End point description |
Biodistribution of In111-labelled anti-CD66 ab after infusion (dosimetry)
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Biodistribution of In111-labelled anti-CD66 ab within 7 days post infusion
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information [1]
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse events were recorded from Study enrolment to 1 year post-stem cell transplant
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Adverse events were described and graded using the National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 4.0).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
NCI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Adverse events RIT phase 1 study
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Children with relapsed/refractory leukaemia undergoing allogeneic haematopoietic stem cell transplant after receiving a infusion of Yttrium-90 labelled anti-CD66 monoclonal antibody, as part of a reduced toxicity conditioning regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: As the Radio Immuno Therapy (RIT) was followed by chemotherapy and an allogeneic haematopoietic stem cell transplant, all children experienced multiple non-serious AEs, as expected. It would be difficult to include them all in this report owing to huge number and as most of these AEs were related to the transplant, rather than the radio-immunotherapy. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||
Substantial protocol amendments (globally) |
|||||||
| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
14 Jul 2015 |
Notification of updated IMPD (IMPD v2, dated 01/02/2015) |
||||||
14 Dec 2016 |
•Update the list of co-investigators and collaborators
•Facilitate the enrolment process
•Clarify the assessment of the dose limiting toxicity
•Reduce the number of bloods to be taken after the transplant (HAMA bloods)
•Facilitate the infusion of IMP1 and IMP2
|
||||||
22 Feb 2018 |
Notification of trial halt due to unavailability of staff to perform scans at UCLH |
||||||
09 Apr 2018 |
Notification of trial restart following staffing issues at UCLH for scans being resolved |
||||||
04 Nov 2018 |
•Amendment seeks approval to change the exclusion criteria from “isolated bone marrow relapse” to just “relapse” in order to allow patients who present with relapses of ALL and AML in other organs to be included in the study.
•Changes to scheduled radiation procedures, i.e. skipping dose level 3 of 50MBq/kg and move to dose level 4 of 55MBq/kg for next cohort.
•Submission of updated protocol/IB/IMPD: Protocol v5 (26/10/2018), IB v8 (31/03/2018), IMPD v4.1 (30/04/2018)
|
||||||
09 Sep 2019 |
The changes relate to a short extension of the storage of the drug substance, CHX A"-DTPA-anti-CD66 monoclonal antibody. |
||||||
Interruptions (globally) |
|||||||
| Were there any global interruptions to the trial? Yes | |||||||
|
|||||||
Limitations and caveats |
|||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| The antibody used in this trial expired before the conclusion of the study, so pateints could not be treated at the highest level of radiation foreseen by the protocol. Neverheless suffieient data was collected to demonstrate lack of toxicity. | |||||||
