Hematological MalignanciesPhase 2NCT03067155
CMV Specific T Cell Therapy After Allogeneic Stem Cell Transplantation.
A Phase 2 study testing CMV-specific T cells and Standard anti-viral therapy in people with Hematological Malignancies and CMV Infection, run by University Hospital, Ghent at 8 sites in Belgium.
Trial summary
Viral infections remain an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), especially after myelo-ablative conditioning and if the donor is antigen-mismatched or haplo-identical.. Read more about this study
- Who is it for?
- Ages 16 to 75 years
- Conditions the study is for
- Hematological Malignancies, CMV Infection
- What is being tested?
- CMV-specific T cells and Standard anti-viral therapy
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 8 sitesBelgium
- Study dates
- Oct 2016to 31 Dec 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 75 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients:
- All underlying diseases that form an indication for allogeneic stem cell transplantation
- Underwent allogeneic stem cell transplantation with a donor that fulfills the following criteria:
- CMV-seropositive at the time of transplant and
- Age 18-70 years 3) Having a CMV reactivation or primary infection or disease with the following characteristics: CMV PCR at least twice positive AND CMV infection relapsing after 3 successful treatment episodes with gancyclovir OR Refractory to treatment with available antiviral drugs which is defined as follows: Persistent positive CMV PCR > detection limit 14 days after initiation of antiviral treatment OR increasing CMV viral load 7 days after initiation of antiviral treatment 4) Informed consent given
- Donor:
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- Is identical to donor of the previous stem cell transplant
- The donor will be pre-screened for the presence of sufficient numbers of CMV-specific T cells:
- IFNgamma producing T cells upon CMVpp65 stimulation are at least twice the background level (unstimulated cells)
- At least 10 events of IFNgamma positive T cells are measured
- IFNgamma producing T cells upon CMVpp65 stimulation are equal or higher than 0,1% of the viable CD4+ and CD8+ cell population If the donor shows sufficient number of circulating CMV-specific cells, according to the test described in 2 3) Only if the donor shows sufficient number of circulating CMV-specific cells, according to the test described in 2:
- Donor has positive IgG serology for CMV, IgM negative or positive
- Donor has signed informed consent for the donation of donor lymphocyte cells
- Donor is found fit for donation by a medical doctor according to selection criteria conform KB annex II (C-2009/18414)
- Donor is negative for infectious disease markers including HCV, HBV and HIV-NAT testing: HBs antigen, HBc/HBs antibodies, Syphilis (TPHA or equivalent), HVC and HIV antibodies.
- Additional testing should be performed and negative when relevant: malaria, west nile virus, trypanosomiasis, HTLV conform KB annex II (C-2009/18414)
- HCG negative within 7 days of apheresis
Who cannot join
- Patients:
- HIV, HCV, HBV positive (HbSAg positivity after vaccination is allowed)
- Life expectancy severely limited by disease other than malignancy or viral infection
- Administration of cytotoxic agent(s) for cytoreduction within three weeks prior to initiation of the treatment or to be expected within 8 weeks after administration of the treatment
- Terminal organ failure except for renal failure (dialysis acceptable)
- Uncontrolled other infection than the one being treated
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- Karnofsky performance score < 60%
- Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment
- Patient is a female who is pregnant or breastfeeding
- Patient with active aGVHD grade 3 or more
- Patient with severe chronic GVHD
- Patient on corticosteroids > 0.5mg/kg. Patient can still be on therapeutic doses of immunosuppressive therapy, but these will be tapered to the lowest possible dose, as is part of standard care in case of CMV reactivation.
- Patient that has received ATG < 1 month prior to infusion or Campath < 1 year prior to infusion
- Any condition not fulfilling inclusion criteria
- Donor:
- Any condition not fulfilling inclusion criteria
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
Belgium8 sites
ZNA Stuivenberg
Antwerp, 2060
AZ Sint-Jan Brugge
Bruges, 8000
Institut Jules Bordet
Brussels, 1000
Universitair Ziekenhuis Brussel
Brussels, 1090
Cliniques Universitaires Saint Luc
Brussels, 1200
Universitair Ziekenhuis Gent
Ghent, Oost-Vlaanderen, 9000
Université de Liège
Liège, 4000
Heilig Hart Ziekenhuis Roeselare
Roeselare, 8800
About this study
Official title: CMV Specific T Cell Therapy for the Treatment of Relapsing or Therapy Refractory CMV Infection After Allogeneic Stem Cell Transplantation With a CMV-positive Donor.
Viral infections remain an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), especially after myelo-ablative conditioning and if the donor is antigen-mismatched or haplo-identical.. In the described setting the patient's own immune system has been destroyed by the necessary highly immuno- and myelo-ablative conditioning and all memory against infections has been deleted. Therefore, there is a high risk for several viral infections and other infectious organisms.Both primary viral infections and reactivations can occur, and patients can become refractory to antiviral treatments, or in some cases an adequate antiviral treatment is unavailable or too toxic. In this study, the investigators will target CMV, as refractory CMV infection and disease is accompanied by an extremely high mortality rate and therefore the development of new treatment approaches is required. Despite the available antiviral drugs, a considerable number of patients are facing an insufficient control of CMV reactivation after SCT. Because reconstitution of CMV-specific T cells confer protection against the development of CMV disease after SCT, attempts have been made to restore antiviral immunity by direct infusion of CMV-specific T cells. Most clinical cellular immunotherapy protocols for CMV treatment have used CMV-specific cytotoxic CD8+ T-cell lines generated by repetitive in vitro stimulation with CMV antigens with success. Despite the proven efficacy, use of cellular therapy in the clinic has been limited, because the approach is time and labor consuming and requires specialized facility allowing handling of the therapeutic cells according to good manufacturing practice. In addition, no sustained response was seen after adoptive transfer that involved only cytotoxic CD8+ T cells. This phenomenon is supported by the fact that recall responses to latent infections depend on the presence of CD4+ T cells to help cytotoxic CD8+ T cells. An alternative approach for the transfer of T-cell immunity is the isolation of Ag-specific T cells ex vivo from the blood of CMV seropositive donors, based on interferon γ (IFN-γ) secretion of T cells after in vitro stimulation with viral Ag, resulting in a combination of CD4+ T helper and cytotoxic CD8+ CMV specific T cells. Using this strategy, a short-term ex vivo protocol was developed for the isolation of pp65 (CMV immunodominant protein)-specific T cells. Since then, several centers have used this protocol in the clinic, infusing low numbers of pp65-specific T cells, that were able to restore protective T-cell immunity against CMV in a post SCT setting in patients with refractory CMV disease or viremia. For this protocol the investigators have set up and validated this method of CMV-specific T-cell generation in the Ghent University Hospital and the investigators will make it available for other Belgian transplant centers.
- Conditions
- Hematological Malignancies, CMV Infection
- Being tested
- CMV-specific T cells, Standard anti-viral therapy
- Keywords
- allogeneic stem cell transplantation, CMV reactivation
- Medical subject headings
- Hematologic Neoplasms, Cytomegalovirus Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CMV-specific T cellsGenetic
Standard anti-viral therapyDrug
Continue with the anti-viral treatment as per standard of care.
| Study group | Role | What they receive |
|---|---|---|
| Treatment group | Experimental | The patients for which a suitable donor product can be obtained will be included in the treatment arm of the protocol. Treatment consists of the administration of CMV-specific T-cells, administered through intravenous transfusion. Depending on response in viral load and GVHD status, a second and/or third administration is possible. Receives: Genetic: CMV-specific T cells |
| Control group | Active comparator | Patients for which the investigator can't obtain a suitable donor product, will be included in the control group consisting of standard anti-viral treatment. Receives: Drug: Standard anti-viral therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of patients for whom the investigator can manufacture a product that meets release criteria, and can therefore receive the product.
Starting from patients and donors that fulfill all inclusion criteria and do not have any exclusion criterium, and donors fulfilling all pre-apheresis criteria.
Measured: Within 1 year after the last follow-up visit of the last patient.
Safety of the administered cell product in terms of Graft-versus-Host-Disease occurence/worsening.
Evaluation of the frequency of patients who develop de novo or recurrent (with a history of (completely recovered)) acute GVHD grade 2 or more or show worsening of an existing aGVHD with at least 1 grade, or emergence of an additional organ involved.
Measured: Within 1 year after the last follow-up visit of the last patient.
Secondary outcomes (5)
Clinical efficacy measured by change in CMV PCR or resolution of CMV disease.
Clinical efficacy has already been shown (albeit not in a randomized phase 3 trial) but as there is no alternative therapy for these patients (except for continuing the therapy they are already getting and to which they are not (longer) responding, this study is not placebo or best supportive care controlled, but is designed as a single arm study. However, by including all patients who can get the product in the treatment arm and those who can't get the product in the observational arm, the study will be able to have a control group without randomization.
Measured: Within 1 year after the last follow-up visit of the last patient.
Evaluation of infusion related adverse event as per CTCAE 4.03.
Measured: Within 1 year after the last follow-up visit of the last patient.
Explore the relationship between the presence of CMV specific T cells in the peripheral blood of the patient and the objective clinical response
Measured: Within 1 year after the last follow-up visit of the last patient.
Make the treatment of relapsing or refractory CMV infection after allogeneic stem cell transplantation with CMV-specific T cell therapy from the CMV positive donor available for patients in Belgium
Measured: Within 1 year after the last follow-up visit of the last patient.
Compare resistance to antiviral therapy in both arms (investigational vs. observational) b measuring change in CMV PCR or evaluating resolution of CMV disease.
Measured: Within 1 year after the last follow-up visit of the last patient.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Mar 2017
- Study startOct 2016
- Primary completion31 Dec 2021
- Study completion31 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hematological MalignanciesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Ghent
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Tessa Kerre, MD, PhD, Principal investigator, University Hospital, Ghent
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03067155
- Sponsor's protocol ID
- BHS-TJT1401
- Other IDs
- 2013-004953-26, BHS-TC13
- Status last verified
- Dec 2022
- First submitted
- 6 Oct 2016
- Last updated
- 21 Dec 2022
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Geurten C, Ghinai R, Munford H, Lawson S. Efficacy of Cytomegalovirus Specific Immunoglobulins to Reduce CMV Reactivation in Pediatric Hematopoietic Stem Cell Transplant Recipients. J Pediatr Hematol Oncol. 2023 Jan 1;45(1):e82-e86. doi: 10.1097/MPH.0000000000002553. Epub 2022 Sep 22.
PubMed 36162011
Study at a glance
From the registry record, last updated by the sponsor on 21 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CMV Specific T Cell Therapy for the Treatment of Relapsing or Therapy Refractory CMV Infection After Allogeneic Stem Cell Transplantation With a CMV-positive Donor.
- ClinicalTrials.gov ID
- NCT03067155
- Acronym / sponsor ID
- BHS-TJT1401
- Conditions
- Hematological Malignancies, CMV Infection
- Keywords
- allogeneic stem cell transplantation, CMV reactivation
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1 participants (actual)
- Lead sponsor
- University Hospital, GhentUniversity, hospital or other
- Study start
- Oct 2016 (actual)
- Primary completion
- 31 Dec 2021 (actual)
- Study completion
- 31 Dec 2021 (actual)
- First posted
- 1 Mar 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Viral infections remain an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), especially after myelo-ablative conditioning and if the donor is antigen-mismatched or haplo-identical.. In the described setting the patient's own immune system has been destroyed by the necessary highly immuno- and myelo-ablative conditioning and all memory against infections has been deleted. Therefore, there is a high risk for several viral infections and other infectious organisms.Both primary viral infections and reactivations can occur, and patients can become refractory to antiviral treatments, or in some cases an adequate antiviral treatment is unavailable or too toxic. In this study, the investigators will target CMV, as refractory CMV infection and disease is accompanied by an extremely high mortality rate and therefore the development of new treatment approaches is required. Despite the available antiviral drugs, a considerable number of patients are facing an insufficient control of CMV reactivation after SCT. Because reconstitution of CMV-specific T cells confer protection against the development of CMV disease after SCT, attempts have been made to restore antiviral immunity by direct infusion of CMV-specific T cells. Most clinical cellular immunotherapy protocols for CMV treatment have used CMV-specific cytotoxic CD8+ T-cell lines generated by repetitive in vitro stimulation with CMV antigens with success. Despite the proven efficacy, use of cellular therapy in the clinic has been limited, because the approach is time and labor consuming and requires specialized facility allowing handling of the therapeutic cells according to good manufacturing practice. In addition, no sustained response was seen after adoptive transfer that involved only cytotoxic CD8+ T cells. This phenomenon is supported by the fact that recall responses to latent infections depend on the presence of CD4+ T cells to help cytotoxic CD8+ T cells. An alternative approach for the transfer of T-cell immunity is the isolation of Ag-specific T cells ex vivo from the blood of CMV seropositive donors, based on interferon γ (IFN-γ) secretion of T cells after in vitro stimulation with viral Ag, resulting in a combination of CD4+ T helper and cytotoxic CD8+ CMV specific T cells. Using this strategy, a short-term ex vivo protocol was developed for the isolation of pp65 (CMV immunodominant protein)-specific T cells. Since then, several centers have used this protocol in the clinic, infusing low numbers of pp65-specific T cells, that were able to restore protective T-cell immunity against CMV in a post SCT setting in patients with refractory CMV disease or viremia. For this protocol the investigators have set up and validated this method of CMV-specific T-cell generation in the Ghent University Hospital and the investigators will make it available for other Belgian transplant centers.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment group | Experimental | Genetic: CMV-specific T cellsThe patients for which a suitable donor product can be obtained will be included in the treatment arm of the protocol. Treatment consists of the administration of CMV-specific T-cells, administered through intravenous transfusion. Depending on response in viral load and GVHD status, a second and/or third administration is possible. |
| Control group | Active comparator | Drug: Standard anti-viral therapyPatients for which the investigator can't obtain a suitable donor product, will be included in the control group consisting of standard anti-viral treatment. |
Who may qualify
- Ages
- 16 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (17 listed)
- Patients:
- CMV-seropositive at the time of transplant and
- Age 18-70 years 3) Having a CMV reactivation or primary infection or disease with the following characteristics: CMV PCR at least twice positive AND CMV infection relapsing after 3 successful treatment episodes with gancyclovir OR Refractory to treatment with available antiviral drugs which is defined as follows: Persistent positive CMV PCR > detection limit 14 days after initiation of antiviral treatment OR increasing CMV viral load 7 days after initiation of antiviral treatment 4) Informed consent given
- Donor:
- IFNgamma producing T cells upon CMVpp65 stimulation are at least twice the background level (unstimulated cells)
Key exclusion criteria (16 listed)
- Patients:
- Donor:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CMV-specific T cells | Genetic | Treatment group |
| Standard anti-viral therapyContinue with the anti-viral treatment as per standard of care. | Drug | Control group |
Primary outcome
Percentage of patients for whom the investigator can manufacture a product that meets release criteria, and can therefore receive the product.
Time frame: Within 1 year after the last follow-up visit of the last patient.
Starting from patients and donors that fulfill all inclusion criteria and do not have any exclusion criterium, and donors fulfilling all pre-apheresis criteria.
Safety of the administered cell product in terms of Graft-versus-Host-Disease occurence/worsening.
Time frame: Within 1 year after the last follow-up visit of the last patient.
Evaluation of the frequency of patients who develop de novo or recurrent (with a history of (completely recovered)) acute GVHD grade 2 or more or show worsening of an existing aGVHD with at least 1 grade, or emergence of an additional organ involved.
5 secondary outcomes
Clinical efficacy measured by change in CMV PCR or resolution of CMV disease.
Time frame: Within 1 year after the last follow-up visit of the last patient.
Evaluation of infusion related adverse event as per CTCAE 4.03.
Time frame: Within 1 year after the last follow-up visit of the last patient.
Explore the relationship between the presence of CMV specific T cells in the peripheral blood of the patient and the objective clinical response
Time frame: Within 1 year after the last follow-up visit of the last patient.
Make the treatment of relapsing or refractory CMV infection after allogeneic stem cell transplantation with CMV-specific T cell therapy from the CMV positive donor available for patients in Belgium
Time frame: Within 1 year after the last follow-up visit of the last patient.
Compare resistance to antiviral therapy in both arms (investigational vs. observational) b measuring change in CMV PCR or evaluating resolution of CMV disease.
Time frame: Within 1 year after the last follow-up visit of the last patient.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Dec 2022.
- Derived from this study: PubMed 36162011Geurten C, Ghinai R, Munford H, Lawson S. Efficacy of Cytomegalovirus Specific Immunoglobulins to Reduce CMV Reactivation in Pediatric Hematopoietic Stem Cell Transplant Recipients. J Pediatr Hematol Oncol. 2023 Jan 1;45(1):e82-e86. doi: 10.1097/MPH.0000000000002553. Epub 2022 Sep 22.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tessa Kerre, MD, PhD principal investigator
University Hospital, Ghent
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing CMV-specific T cells and Standard anti-viral therapy in people with Hematological Malignancies and CMV Infection, run by University Hospital, Ghent at 8 sites in Belgium.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of patients for whom the investigator can manufacture a product that meets release criteria, and can therefore receive the product. (time frame: Within 1 year after the last follow-up visit of the last patient.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03067155, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Dec 2022.