Clinical Trial Results:
Dendritic cell vaccination in patients with Lynch Syndrome or colorectal cancer with MSI
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Summary
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EudraCT number |
2008-005584-33 |
Trial protocol |
NL |
Global end of trial date |
02 Nov 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Dec 2020
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First version publication date |
04 Dec 2020
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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 |
KUN2009
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01885702 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Radboudumc
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Sponsor organisation address |
Geert Grooteplein Zuid 10, Nijmegen, Netherlands, 6525 GA
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Public contact |
Prof. dr. N. Hoogerbrugge, Radboudumc, department of Human Genetics, 0031 2466205, nicoline.hoogerbrugge@radboudumc.nl
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Scientific contact |
Prof. dr. I.J.M. de Vries, Radboudumc, department of Tumor Immunology, 0031 2455750, jolanda.devries@radboudumc.nl
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Nov 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Jun 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Nov 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 |
The primary objective of the study is to investigate the safety and feasibility of vaccination with frameshift-derived neoantigen-loaded DC.
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Protection of trial subjects |
Adverse events are defined as any undesirable experience occurring to a subject during a clinical trial, whether or not considered related to the investigational treatment. All adverse events (AE) occurring during the study, whether or not definitely attributable to the immunization procedure, will be recorded. Any CTC-grade 4 or other serious, life-threatening or fatal adverse event occurring within 28 days of receiving the last treatment must be reported within 24 hours to the study coordinator.
A serious adverse event is any untoward medical occurrence or effect that results in death;
- is life threatening (at the time of the event);
- requires hospitalisation or prolongation of existing inpatients’ hospitalisation;
- results in persistent or significant disability or incapacity;
- is a congenital anomaly or birth defect;
- is a new event of the trial likely to affect the safety of the subjects, such as an unexpected outcome of an adverse reaction, lack of efficacy of the treatment of a life threatening disease, major safety finding from a newly completed animal study, etc.
All SAEs will be reported to the accredited CMO that approved the protocol, according to the requirements of that CMO.
All AEs will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist.
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Background therapy |
Colorectal cancer is one of the most common types of cancer in the western world. Surgery offers the only change for cure. Approximately 50% of patients eventually develop distant metastases for which no curative treatment is available, with the exception of a small subgroup of patients with resectable metastases. The results of systemic treatment improve progression free survival by about 2 years, but there remains a need for more effective treatment. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Dec 2010
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Scientific research | ||
Long term follow-up duration |
4 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Netherlands: 23
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Worldwide total number of subjects |
23
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EEA total number of subjects |
23
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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) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
22
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
- All individuals were HLA-A2.1 positive - Patients who had any malignancy, more than 5 years previously, were also eligible - WHO performance status 0-1 - Absence of autoimmune diseases, an active viral infection or allergy to shell fish - No concomitant immunosuppressive drug usen - No pregnancy or lactation - No laboratory abnormalities | ||||||||||||
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Pre-assignment
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Screening details |
There was no run-in period for this trial. | ||||||||||||
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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 |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||
Blinding implementation details |
Not applicable.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Lynch syndrome patients with MSI CRC | ||||||||||||
Arm description |
CRC patients, who are known to carry a germline MMR-gene mutation (Lynch syndrome) and patients with an MSI-positive CRC and yet unknown or negative MMR-gene mutation status | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Vaccination with dendritic cells loaded with CEA-derived and frameshift mutation-derived neopeptides
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Investigational medicinal product code |
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Other name |
moDC vaccine
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use, Subdermal use
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Dosage and administration details |
DC vaccination with DC loaded with KLH and tumor-associated peptide CEA and frameshift-derived neopeptides will be administered three times on day 0, 7 and 14. DC will be simultaneously administered intradermally (i.d.) in the upper leg and intravenously (i.v.). This regime is comparable to our previous trials in colorectal cancer patients. We aim to inject 10 and 20 x 106 cells intradermal and intraveneously, respectively.
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Arm title
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Carriers of a germline MMR-gene mutation | ||||||||||||
Arm description |
Persons (n=20) who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet or were more than 5 years beyond primary CRC resection at the time of the study . These latter persons know that they have a life-time risk for CRC up to 70% because of a germline mutation in one of the MMR-genes, are highly motivated to participate in studies that may lead to risk reduction, because they experienced colorectal cancer and death with close relatives. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Vaccination with dendritic cells loaded with CEA-derived and frameshift mutation-derived neopeptides
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Investigational medicinal product code |
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Other name |
moDC vaccine
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use, Subdermal use
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Dosage and administration details |
DC vaccination with DC loaded with KLH and tumor-associated peptide CEA and frameshift-derived neopeptides will be administered three times on day 0, 7 and 14. DC will be simultaneously administered intradermally (i.d.) in the upper leg and intravenously (i.v.). This regime is comparable to our previous trials in colorectal cancer patients. We aim to inject 10 and 20 x 106 cells intradermal and intraveneously, respectively.
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: This milestone is applicable to arm A only. In arm B all 20 planned patients were included. |
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Baseline characteristics reporting groups
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Reporting group title |
Lynch syndrome patients with MSI CRC
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Reporting group description |
CRC patients, who are known to carry a germline MMR-gene mutation (Lynch syndrome) and patients with an MSI-positive CRC and yet unknown or negative MMR-gene mutation status | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Carriers of a germline MMR-gene mutation
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Reporting group description |
Persons (n=20) who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet or were more than 5 years beyond primary CRC resection at the time of the study . These latter persons know that they have a life-time risk for CRC up to 70% because of a germline mutation in one of the MMR-genes, are highly motivated to participate in studies that may lead to risk reduction, because they experienced colorectal cancer and death with close relatives. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Lynch syndrome patients with MSI CRC
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Reporting group description |
CRC patients, who are known to carry a germline MMR-gene mutation (Lynch syndrome) and patients with an MSI-positive CRC and yet unknown or negative MMR-gene mutation status | ||
Reporting group title |
Carriers of a germline MMR-gene mutation
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Reporting group description |
Persons (n=20) who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet or were more than 5 years beyond primary CRC resection at the time of the study . These latter persons know that they have a life-time risk for CRC up to 70% because of a germline mutation in one of the MMR-genes, are highly motivated to participate in studies that may lead to risk reduction, because they experienced colorectal cancer and death with close relatives. | ||
Subject analysis set title |
Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The first objective of this study is to evaluate safety and feasibility of vaccination with frameshift-derived neoantigen-loaded DC.
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Subject analysis set title |
Feasibility
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The first objective of this study is to evaluate safety and feasibility of vaccination with frameshift-derived neoantigen-loaded DC.
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Subject analysis set title |
Induction of antigen-specific T cells
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The secondary objectives of the study are to evaluate whether peptide-loaded DC can induce or enhance an immune response to tumor-associated antigen CEA and specific frameshift-derived neoantigens in the study population
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End point title |
Safety [1] | ||||||||||||||||
End point description |
AEs are defined as any undesirable experience occurring to a subject during a clinical trial, whether or not considered related to the investigational treatment. All AEs occurring during the study, whether or not definitely attributable to the immunization procedure, will be recorded. Any CTC-grade 4 or other serious, life-threatening or fatal adverse event occurring within 28 days of receiving the last treatment must be reported within 24 hours to the study coordinator.
All AEs will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist.
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End point type |
Primary
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End point timeframe |
From inclusion until any occured AE has been abated, or until a stable situation has been reached.
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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: For this safety endpoint no statistical analysis were performed. |
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Attachments |
Safety and feasibility description |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Feasibility [2] | ||||||||||||||||
End point description |
Individuals were included during the periode from February 2012 until January 2014 (arm A). And during the period from January 2014 until November 2014 (arm B).
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End point type |
Primary
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End point timeframe |
From February 2012 until January 2014 (arm A). And from January 2014 until November 2014 (arm B).
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| Notes [2] - 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: For this feasibility endpoint no statistical analysis were performed. |
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Attachments |
Safety and feasibility description |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Induction of antigen-specific T cells | ||||||||||||||||
End point description |
Patients were vaccinated intravenously and intradermally 3 times every week with DC loaded with CEA-derived and frameshift mutation-derived neopeptides. After the 3 vaccinations a DTH was performed, from which biopsies will be taken for T cell analysis. If no relapse occurs, we will repeat this cycle two more times with a 6 months interval.
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End point type |
Secondary
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End point timeframe |
During the period of 3 DC vaccination cycles (if no relapse occurs).
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Statistical analysis title |
Paired t-tests | ||||||||||||||||
Statistical analysis description |
Descriptive statistics of the immunological responses for the treated group were calculated using SPSS® Statistics version 20.0 software (SPSS Inc., Chicago, IL, USA) and Graphpad Prism 5.03 (GraphPad Software, Inc., San Diego, CA, USA). Statistical significance was evaluated using the log-rank test and was defined as P< 0.05. Paired t-tests were performed to evaluate immunologic responses before and after vaccination.
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Comparison groups |
Lynch syndrome patients with MSI CRC v Carriers of a germline MMR-gene mutation v Induction of antigen-specific T cells
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Confidence interval |
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| Notes [3] - Immunogical responses were studied before and after vaccination. Therefore, the subjects in this analysis are 46 (two times 23 patients). |
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Adverse events information
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Timeframe for reporting adverse events |
From study inclusion until disappearence of an AE. All AEs will be followed until they have abated, or until a stable situation has been reached.
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Adverse event reporting additional description |
All AEs occurring during the study, whether or not definitely attributable to the vaccines, will be recorded. Any CTCAE grade 4 or other serious, life-threatening or fatal adverse event occurring within 28 days of receiving the last treatment must be reported within 24 hours to the study coordinator. All AEs will be followed until they have abated.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||
Dictionary version |
3.0
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Reporting groups
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Reporting group title |
Any toxicity (overall patients)
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Reporting group description |
Any adverse event. | ||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||
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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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09 Jul 2013 |
Despite a number of measures, the inclusion of the first 5 patients (arm A) has been delayed. As a result, the inclusion criteria have been broadened and patients have been approached from a larger area (more hospitals) to participate in the study. Nevertheless, we were unable to include the required 5 patients. Therefore, only 3 patients were included. DC vaccinations in these first 3 patients were safe and no CTCAE grade 3-4 toxicity was observed.
Consequently, we amended the protocol and asked for permission to start with the enrollment of of the Lynch syndrome carriers (arm B) after treatment of 3 in stead of 5 patients in arm A. This amendment was accepted by the medical ethical committee and we started with patient recruitment in arm B of the study. |
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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. | |||
| Despite a number of measures, the inclusion of the first 5 patients (arm A) failed. Therefore, only 3 patients were included. | |||
