CD19 Positive Non-Hodgkin LymphomaPhase 1CD19NCT01493453
A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy
A Phase 1 study testing aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine in people with CD19 Positive Non-Hodgkin Lymphoma, run by The Christie NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
In particular circumstances T cells can be an effective treatment for malignant disease, for example, donor lymphocyte infusions following allogeneic transplants or treatment of EBV related lymphomas post allograft. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- CD19 Positive Non-Hodgkin Lymphoma
- What is being tested?
- aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Mar 2008to Jun 2019
- Phase
- Phase 1
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have histologically confirmed CD19 positive non-Hodgkin Lymphoma with evidence of persistent or progressive disease and poor prognosis as discussed in detail in section 1.5
- Written informed consent and the ability of the patient to co-operate with study treatment, procedures and follow up must be ensured and documented.
- Age equal to or greater than 18 years.
- World Health Organisation (WHO) performance status of 0 or 1 (appendix 1).
- Life expectancy >3months.
- LVEF > 50% as measured by MUGA scan
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- Haematological and biochemical indices:
- Haemoglobin (Hb)≥ 10.0 g/dl neutrophils ≥ 1.0 x 109/L platelets (Plts)≥ 100 x 109/L
- Any of the following abnormal baseline liver function tests:
- serum bilirubin ≤ 1.5 x upper limit of normal (ULN) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and /or alkaline phosphatase (ALP)≤ 5 x ULN Serum creatinine ≤ 0.14 mmol/L
- Female patients of child-bearing potential are eligible, provided they have a negative serum or urine pregnancy test prior to enrolment and agree to use appropriate medically approved contraceptive precautions for four weeks prior to entering the trial, during the trial, and for six months afterwards.
- Male patients must agree to use barrier method contraception during the trial and for six months afterwards.
- Measurable disease as defined by RECIST criteria (appendix 3).
Who cannot join
- Radiotherapy, biological therapy, endocrine therapy, immunotherapy, systemic steroids, or chemotherapy during the previous four weeks (six weeks for nitrosoureas and Mitomycin-C) prior to treatment or during the course of the trial.
- All toxic manifestations of previous treatment must have resolved. Exceptions to this are alopecia or certain Grade 1 toxicities which in the opinion of the Investigator and Trial Sponsor should not exclude the patient.
- Participation in any other clinical trial within the previous 30 days or during the course of this trial.
- Previous participation in a Gene Therapy trial.
- Previous allogeneic transplant.
- Patients who are high medical risks because of non-malignant systemic disease, including those with active infection, uncontrolled cardiac or respiratory disease, or other serious medical or psychiatric disorders which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
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- Concurrent serious infections within the 28 days prior to entry to the trial.
- Current malignancies at other sites, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.
- Patients known or found to be serologically positive for Hepatitis B, C, HIV or HTLV.
- History of autoimmune disease.
- Evidence of CNS involvement.
- Patients who are likely to require systemic steroids or other immunosuppressive therapy.
- Pregnant and lactating women.
- Radiotherapy to >25% skeleton.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
The Christie NHS Foundation Trust
Manchester, M20 3EE
About this study
Official title: A Phase I Study of Adoptive Transfer of Autologous Tumour Antigen-Specific T Cells With Pre-conditioning Chemotherapy and Intravenous IL2 in Patients With CD19 Positive Malignancy
In particular circumstances T cells can be an effective treatment for malignant disease, for example, donor lymphocyte infusions following allogeneic transplants or treatment of EBV related lymphomas post allograft. However, many common cancers are poorly recognised by the immune system in part because of a lack of suitable T cell targets and in part because of defects in antigen presentation by tumours (Garrido, et al 1997). Genetically modified T cells engineered to express chimeric immune receptors (CIRs) on their cell surface can bypass the need for MHC presentation and thus represent an attractive approach to immunotherapy (Gross, et al 1989).
Read the detailed description
CD19 is an Immunoglobulin-like 95kDa glycoprotein that is expressed on all B lymphocytes until differentiation into terminal effector cells (Tedder and Isaacs 1989). It plays an important role in regulating cell signalling thresholds and also as a costimulatory molecule for B cell receptor signalling (Tedder, et al 1997). CD19 is present on the majority of B-CLL, B-ALL, and both low and high grade non-Hodgkin lymphomas (NHL). It is rarely lost during the process of neoplastic transformation and is not expressed on haematopoetic stem cells. B cell malignancies are often highly responsive to chemotherapy, with cures possible in significant numbers of those with high grade tumours. However, improved treatments are needed for those with low grade tumours and those with high grade tumours who relapse after conventional therapy.
In recent years the introduction of Rituximab, a CD20 monoclonal antibody, into clinical practice has increased the options available for the treatment of NHL (Maloney, et al 1994). The success of Rituximab and other monoclonal antibodies has demonstrated that B cell malignancies may be particularly suitable as a target for immunotherapy. However, there are number of potential advantages of T cells engineered to express a CIR over monoclonal antibody therapies. Firstly, the possibility of in vivo T cell persistence and expansion may enable stable expression of the CIR over a prolonged period of time (Walker, et al 2000). Secondly, homing to the tumour site may mean that T cells need not rely on diffusion to achieve localisation (Balkwill 2004, Mitsuyasu, et al 2000) and thirdly following tumour recognition T cells can produce cytokines that may recruit and activate other effector cells. An alternative to CIR engineered T cells is the generation of peptide specific T cells. Lymphoma models suggest these can be effective (Armstrong, et al 2002, Armstrong, et al 2004), but to produce clinically applicable numbers of T cells is technically demanding and there is a lack of generic peptide target antigens in lymphoma.
One potential problem in the use of CIR engineered T cells in general is that tumour associated antigens are frequently expressed at low levels on normal tissues, thus providing the potential for autoimmunity. Targeting B cell malignancies with CD19 specific T cells is attractive because whilst CD19 is expressed on B cells and the majority of B cell malignancies it is not expressed on any other cell type. It is clear from clinical use of anti-CD20 antibodies that prolonged depletion of B cells (>6 months) is safe (Plosker and Figgitt 2003) and that even in patients with hereditary B cell deficiency immunoglobulin infusion restores normal health in most patients (Ochs and Smith 1996).
The Investigators have therefore propose a clinical trial using T cells expressing a CD19 targeting CIR by retroviral transduction of the CIR into activated T cells in order to target B cell malignancies.
- Conditions
- CD19 Positive Non-Hodgkin Lymphoma
- Being tested
- aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
aCD19z cells, IL2, pre conditioning Cyclophosphamide & FludarabineGenetic
aCD19z T cells IV Day 1. The dose of aCD19z T cells will be determined by dose escalation scheme, starting at 10*9 IL2 given as 15 minute IV infusion every eight hours for up to 12 doses Cyclophosphamide (C) 15mg/kg day -7 and day -6, Fludarabine (F) 25mg/m2 day -5 to day -1.
| Study group | Role | What they receive |
|---|---|---|
| Single Arm - aCD19z cells, interleukin 2, Chemotherapy | Experimental | Not described Receives: Genetic: aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
To asses aCD19z T cell survival and aCD19z T cell toxicity in patients, & The dose of aCD19z T cells required to give optimal survival of these cells in the circulation
Measured: Week 6
Secondary outcomes (1)
To assess whether aCD19z T cells in the circulation are functional
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Dec 2011 (estimated)
- Study startMar 2008
- Primary completionDec 2014
- Study completionJun 2019
Why it stopped: Investigation into serious breach
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for CD19 Positive Non-Hodgkin LymphomaStudies 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 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Christie NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01493453
- Sponsor's protocol ID
- 05_DOG05_18
- Acronym
- CD19
- Status last verified
- Apr 2023
- First submitted
- 14 Dec 2011
- Last updated
- 19 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 19 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study of Adoptive Transfer of Autologous Tumour Antigen-Specific T Cells With Pre-conditioning Chemotherapy and Intravenous IL2 in Patients With CD19 Positive Malignancy
- ClinicalTrials.gov ID
- NCT01493453
- Acronym / sponsor ID
- CD19 / 05_DOG05_18
- Conditions
- CD19 Positive Non-Hodgkin Lymphoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Investigation into serious breach
- Enrolment
- 17 participants (actual)
- Lead sponsor
- The Christie NHS Foundation TrustUniversity, hospital or other
- Study start
- Mar 2008
- Primary completion
- Dec 2014 (actual)
- Study completion
- Jun 2019 (actual)
- First posted
- 16 Dec 2011 (estimated)
- 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.
In particular circumstances T cells can be an effective treatment for malignant disease, for example, donor lymphocyte infusions following allogeneic transplants or treatment of EBV related lymphomas post allograft. However, many common cancers are poorly recognised by the immune system in part because of a lack of suitable T cell targets and in part because of defects in antigen presentation by tumours (Garrido, et al 1997). Genetically modified T cells engineered to express chimeric immune receptors (CIRs) on their cell surface can bypass the need for MHC presentation and thus represent an attractive approach to immunotherapy (Gross, et al 1989).
Detailed description
CD19 is an Immunoglobulin-like 95kDa glycoprotein that is expressed on all B lymphocytes until differentiation into terminal effector cells (Tedder and Isaacs 1989). It plays an important role in regulating cell signalling thresholds and also as a costimulatory molecule for B cell receptor signalling (Tedder, et al 1997). CD19 is present on the majority of B-CLL, B-ALL, and both low and high grade non-Hodgkin lymphomas (NHL). It is rarely lost during the process of neoplastic transformation and is not expressed on haematopoetic stem cells. B cell malignancies are often highly responsive to chemotherapy, with cures possible in significant numbers of those with high grade tumours. However, improved treatments are needed for those with low grade tumours and those with high grade tumours who relapse after conventional therapy.
In recent years the introduction of Rituximab, a CD20 monoclonal antibody, into clinical practice has increased the options available for the treatment of NHL (Maloney, et al 1994). The success of Rituximab and other monoclonal antibodies has demonstrated that B cell malignancies may be particularly suitable as a target for immunotherapy. However, there are number of potential advantages of T cells engineered to express a CIR over monoclonal antibody therapies. Firstly, the possibility of in vivo T cell persistence and expansion may enable stable expression of the CIR over a prolonged period of time (Walker, et al 2000). Secondly, homing to the tumour site may mean that T cells need not rely on diffusion to achieve localisation (Balkwill 2004, Mitsuyasu, et al 2000) and thirdly following tumour recognition T cells can produce cytokines that may recruit and activate other effector cells. An alternative to CIR engineered T cells is the generation of peptide specific T cells. Lymphoma models suggest these can be effective (Armstrong, et al 2002, Armstrong, et al 2004), but to produce clinically applicable numbers of T cells is technically demanding and there is a lack of generic peptide target antigens in lymphoma.
One potential problem in the use of CIR engineered T cells in general is that tumour associated antigens are frequently expressed at low levels on normal tissues, thus providing the potential for autoimmunity. Targeting B cell malignancies with CD19 specific T cells is attractive because whilst CD19 is expressed on B cells and the majority of B cell malignancies it is not expressed on any other cell type. It is clear from clinical use of anti-CD20 antibodies that prolonged depletion of B cells (>6 months) is safe (Plosker and Figgitt 2003) and that even in patients with hereditary B cell deficiency immunoglobulin infusion restores normal health in most patients (Ochs and Smith 1996).
The Investigators have therefore propose a clinical trial using T cells expressing a CD19 targeting CIR by retroviral transduction of the CIR into activated T cells in order to target B cell malignancies.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single Arm - aCD19z cells, interleukin 2, Chemotherapy | Experimental | Genetic: aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Patients must have histologically confirmed CD19 positive non-Hodgkin Lymphoma with evidence of persistent or progressive disease and poor prognosis as discussed in detail in section 1.5
- Written informed consent and the ability of the patient to co-operate with study treatment, procedures and follow up must be ensured and documented.
- Age equal to or greater than 18 years.
- World Health Organisation (WHO) performance status of 0 or 1 (appendix 1).
- Life expectancy >3months.
Key exclusion criteria (14 listed)
- Radiotherapy, biological therapy, endocrine therapy, immunotherapy, systemic steroids, or chemotherapy during the previous four weeks (six weeks for nitrosoureas and Mitomycin-C) prior to treatment or during the course of the trial.
- All toxic manifestations of previous treatment must have resolved. Exceptions to this are alopecia or certain Grade 1 toxicities which in the opinion of the Investigator and Trial Sponsor should not exclude the patient.
- Participation in any other clinical trial within the previous 30 days or during the course of this trial.
- Previous participation in a Gene Therapy trial.
- Previous allogeneic transplant.
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 |
|---|---|---|
| aCD19z cells, IL2, pre conditioning Cyclophosphamide & FludarabineaCD19z T cells IV Day 1. The dose of aCD19z T cells will be determined by dose escalation scheme, starting at 10*9 IL2 given as 15 minute IV infusion every eight hours for up to 12 doses Cyclophosphamide (C) 15mg/kg day -7 and day -6, Fludarabine (F) 25mg/m2 day -5 to day -1. | Genetic | Single Arm - aCD19z cells, interleukin 2, Chemotherapy |
Primary outcome
To asses aCD19z T cell survival and aCD19z T cell toxicity in patients, & The dose of aCD19z T cells required to give optimal survival of these cells in the circulation
Time frame: Week 6
1 secondary outcome
To assess whether aCD19z T cells in the circulation are functional
Time frame: 6 weeks
Results and safety
The study was stopped early (reason given: Investigation into serious breach). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Apr 2023.
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine in people with CD19 Positive Non-Hodgkin Lymphoma, run by The Christie NHS Foundation Trust at 1 site in United Kingdom.
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 13 inclusion and 14 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: stopped early, as of the sponsor's last update on 19 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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 was stopped early (reason given: Investigation into serious breach). Results are not available in the source record.
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?
To asses aCD19z T cell survival and aCD19z T cell toxicity in patients, & The dose of aCD19z T cells required to give optimal survival of these cells in the circulation (time frame: Week 6). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 19 Apr 2023.