Follicular LymphomaPhase 2NCT01329354
Rituximab and Autologous Effector Lymphocytes in Non-Hodgkin Follicular Lymphoma in Response to First Line Chemotherapy
A Phase 2 study testing Autologous effector lymphocytes expanded ex-vivo in people with Follicular Lymphoma and Follicular Non-Hodgkin´s Lymphoma, run by Clinica Universidad de Navarra, Universidad de Navarra at 1 site in Spain.
Trial summary
Nowadays, therapy with monoclonal antibodies is considered to be a standard treatment that increases the rate of remissions and the overall survival in patients with follicular lymphoma. Nevertheless there are an important number of patients who do not benefit from this therapy. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Follicular Lymphoma, Follicular Non-Hodgkin´s Lymphoma, Autologous Effector Lymphocytes
- What is being tested?
- Autologous effector lymphocytes expanded ex-vivo
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 1 siteSpain
- Study dates
- Mar 2011to Nov 2019
- 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 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with histologically-confirmed follicular lymphoma CD20-positive grade 1, 2 ó 3a.
- Patients with aptitude to sign the written informed consent and to express his desire to fulfill all the requirements of the protocol during the period of study.
- Patients not treated before. The induction treatment with rituximab and chemotherapy must be the first line for the patients who are included in the study.
- Patients undergoing maintenance therapy with rituximab every two/three months.
- Ann Arbor stage II, III o IV before receiving the induction treatment with rituximab and chemotherapy.
- The patient must have achieved a partial or complete response based on the revised International Workshop Response Criteria (IWRC) (Cheson, et al 2007) following the induction treatment.
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- Age >18 years and <75 years.
- Performance status <2 following the Eastern Cooperative Oncology Group (ECOG).
- Screening laboratory values obtained 28 days before registry (unless due to lymphoma involvement of the bone marrow): Hemoglobin > 8,0 g/dL (5,0 mmol/L), Neutrophil absolute count > 1,5 x 109/L,Platelets > 100 x 109/L
Who cannot join
- Patients with transformed follicular lymphoma into diffuse large B-cell lymphoma.
- Patients with evidence of follicular lymphoma grade 3b.
- Patients with evidence of primary cutaneous or gastrointestinal follicular lymphoma.
- Patients with evidence of current central nervous system involvement.
- Patients who received previous induction treatment other than rituximab and chemotherapy.
- Patients receiving chronic immunosuppressive agents in the last 4 weeks. Patients may be receiving stable chronic doses of corticosteroids with a maximum dose of 20 mg/day of prednisone or equivalent.
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- Patients who have a history of another primary malignancy < 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix.
- Decompensated renal function: serum creatininea > 2,0 mg/dL (197 u.mol/L.
- Decompensated hepatic function: total bilirrubine > 2,0 mg/dL (34 umol/L), AST (SGOT) > 3 x ULN, unless due to lymphoma involvement
- Patients with a known history of human immunodeficiency virus (HIV) seropositivity, chronic hepatitis or other active viral infections due to hepatitis B virus (HBV) or hepatitis C virus (HVC).
- Patients with underlying serious diseases that in the criteria of the investigator could concern the capacity of the patient to take part in the test (for example, infection in process, not controlled diabetes mellitus, gastric ulcers, autoimmune active disease).
- Life expectancy <6 months.
- Female patients who are pregnant or breast feeding.
- Patients with known hypersensitivity to rituximab or other murine proteins or to any of the excipients.
- Patients who are using other investigational agents or who have received investigational drus 30 days prior to study drug start.
- Any other medical or psychological coexistent condition that rejects the participation in the study or compromises the aptitude to give the informed consent.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase II Clinical Trial of Immunotherapy With Rituximab and Autologous Effector Lymphocytes in Patients With Non-Hodgkin Follicular Lymphoma in Response to First Line Chemotherapy
Nowadays, therapy with monoclonal antibodies is considered to be a standard treatment that increases the rate of remissions and the overall survival in patients with follicular lymphoma. Nevertheless there are an important number of patients who do not benefit from this therapy. A way to improve the efficiency of monoclonal antibodies therapy could be to improve the activity of the effector arm of the immune system. A strategy that has been proposed to obtain this improvement is the utilization of lymphocyte activated killer (LAK) cells. In addition, the combination of LAK cells with monoclonal antibodies might obtain an additive effect across the stimulation of the antibody dependent cellular cytotoxicity (ADCC)activity.
The present clinical assay proposes to study the feasibility, safety and effectiveness of treatment with autologous effector cells expanded ex vivo associated with a standard maintenance treatment with rituximab in patients with follicular lymphoma in remission after first-line treatment. In addition, we plan to analyse various biological parameters that can predict the susceptibility of patients to treatment with rituximab. Specifically, we propose to study the polymorphisms of Fc receptor, polymorphisms related to the ability of complement activation, to study both the complement activity and peripheral blood cell subpopulations that can mediate directly or indirectly dependent antibody cytotoxic effect. We will also try to correlate any of these biological parameters with the response to treatment.
Read the detailed description
There are many mechanisms involved in the antitumor effect of the antibodies including the induction of apoptosis, blocking angiogenesis, blockade of intracellular signaling pathways, and activation of complement leading to lysis of tumor cells. However it appears that the antibody-dependent cellular cytotoxicity (ADCC) is one of the predominant mechanisms of action. It is important to note that in order to obtain a powerful ADCC effect it is necessary the action of the antibody but also the activity of the effector cell, and thus the competence of the immune system of the guest. There are different cellular subpopulations that mediate the ADCC effect. CTL and NK are two of these subpopulations that can be reduced in patients with cancer.
A way to improve the efficiency of the monoclonal antibodies would be to improve the activity of the effector arm of the immune system. A strategy that that has been planed is the utilization of LAK cells. The culture of lymphocytes of peripheral blood with IL-2 activates the subpopulations of killer cells. This population of killer cells activated with cytokines (LAK: lymphokine activated killer) has a high number of NK and CTL cells, both with increased cytotoxic capacity. It has been demonstrated that the immunotherapy with LAK cells might be an effective and sure treatment for patients with follicular lymphoma.
In a murine model it has been demonstrated that LAK cells associated with monoclonal antibodies increase the antitumoral activity when compared to the administration of antibodies alone. In addition, in this model the combination was also superior to the administration of monoclonal antibodies + IL-2 (Schultz et al., 1990). Other investigators have demonstrated similar results. This information supports the idea of the combined therapy consisting in LAK with anti-CD20 antibodies. This therapy can induce a destruction of CD20 positive cells greater than that with the monoclonal antibodies alone. In addition, it has been reported that the administration of systemic IL-2 and LAK cells improves the ADCC in lymphoma patients treated with rituximab. It is a small pilot study, with 10 patients. Seven of them received LAK cells following a programmed way. The safety of the treatment and the promising results demonstrated in this study encourage to investigate in this line.
Since one of the mechanisms of action of the monoclonal antibodies is to promote ADCC , our hypothesis is that the treatment with a suspension of autologous effector lymphocytes expanded ex-vivo with culture should modify the biological effect of the treatment with rituximab in follicular lymphoma patients, with an acceptable safety profile, and probably increasing the efficiency of the monoclonal antibodies. In order to evaluate this hypotesis we propose an open, prospective, historically controlled, phase II clinical study in patients with follicular lymphoma who have achieved a remission after first-line therapy including the anti-CD20 monoclonal antibody rituximab and chemotherapy.
- Being tested
- Autologous effector lymphocytes expanded ex-vivo
- Keywords
- Follicular lymphoma, Follicular non-Hodgkin´s lymphoma, Autologous effector lymphocytes, Cell Therapy, Maintenance therapy, Rituximab
- Medical subject headings
- Lymphoma, Follicular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Autologous effector lymphocytes expanded ex-vivoBiological
Also called LAK, LAK cells, Activated lymphocytes
Maintenance therapy with Rituximab every two months is the standard of care for patients with follicular lymphoma after induction therapy. The intervention consists on the administration of autologous effector lymphocytes expanded ex-vivo every two Rituximab administrations.
| Study group | Role | What they receive |
|---|---|---|
| Autologous effector lymphocytes | Experimental | Not described Receives: Biological: Autologous effector lymphocytes expanded ex-vivo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression free survival (PFS) from the entry in the study.
The PFS is defined as the time from the entry in the study up to the progression of the disease.
Measured: 01/03/2015
Secondary outcomes (4)
Event free survival from the entry in the study
Event: progression, relapse, death for any reason, or institution of a new anti-lymphoma treatment (chemotherapy, radiotherapy or immunotherapy).
Measured: 01/03/2015
Time to the next anti-lymphoma treatment
Defined as the time from the registry of the patient up to the institution of a new regimen (chemotherapy, radiotherapy or immunotherapy).
Measured: 01/03/2015
Disease free survival
Defined as the time from the first complete response documented up to the relapse
Measured: 01/03/2015
Safety
Defined as the incidence of toxicity of all the treatments.
Measured: 01/01/2012
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Apr 2011 (estimated)
- Study startMar 2011
- Primary completionNov 2019 (estimated)
- Study completionNov 2019 (estimated)
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 Follicular 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 38 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Clinica Universidad de Navarra, Universidad de Navarra
- Sponsor type
- University, hospital or other
- Collaborators
- Spanish National Health System
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01329354
- Sponsor's protocol ID
- LFNK
- Other IDs
- 2009-017829-19, 2009
- Status last verified
- Oct 2017
- First submitted
- 1 Apr 2011
- Last updated
- 24 Oct 2017
- Results posted
- No
- Data monitoring committee
- No
Publications
Garcia-Munoz R, Lopez-Diaz-de-Cerio A, Feliu J, Panizo A, Giraldo P, Rodriguez-Calvillo M, Grande C, Pena E, Olave M, Panizo C, Inoges S. Follicular lymphoma: in vitro effects of combining lymphokine-activated killer (LAK) cell-induced cytotoxicity and rituximab- and obinutuzumab-dependent cellular cytotoxicity (ADCC) activity. Immunol Res. 2016 Apr;64(2):548-57. doi: 10.1007/s12026-015-8747-9.
PubMed 26659089
Study at a glance
From the registry record, last updated by the sponsor on 24 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Clinical Trial of Immunotherapy With Rituximab and Autologous Effector Lymphocytes in Patients With Non-Hodgkin Follicular Lymphoma in Response to First Line Chemotherapy
- ClinicalTrials.gov ID
- NCT01329354
- Acronym / sponsor ID
- LFNK
- Keywords
- Follicular lymphoma, Follicular non-Hodgkin´s lymphoma, Autologous effector lymphocytes, Cell Therapy, Maintenance therapy, Rituximab
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 38 participants (estimated)
- Lead sponsor
- Clinica Universidad de Navarra, Universidad de NavarraUniversity, hospital or other
- Collaborators
- Spanish National Health System
- Study start
- Mar 2011
- Primary completion
- Nov 2019 (estimated)
- Study completion
- Nov 2019 (estimated)
- First posted
- 5 Apr 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.
Nowadays, therapy with monoclonal antibodies is considered to be a standard treatment that increases the rate of remissions and the overall survival in patients with follicular lymphoma. Nevertheless there are an important number of patients who do not benefit from this therapy. A way to improve the efficiency of monoclonal antibodies therapy could be to improve the activity of the effector arm of the immune system. A strategy that has been proposed to obtain this improvement is the utilization of lymphocyte activated killer (LAK) cells. In addition, the combination of LAK cells with monoclonal antibodies might obtain an additive effect across the stimulation of the antibody dependent cellular cytotoxicity (ADCC)activity.
The present clinical assay proposes to study the feasibility, safety and effectiveness of treatment with autologous effector cells expanded ex vivo associated with a standard maintenance treatment with rituximab in patients with follicular lymphoma in remission after first-line treatment. In addition, we plan to analyse various biological parameters that can predict the susceptibility of patients to treatment with rituximab. Specifically, we propose to study the polymorphisms of Fc receptor, polymorphisms related to the ability of complement activation, to study both the complement activity and peripheral blood cell subpopulations that can mediate directly or indirectly dependent antibody cytotoxic effect. We will also try to correlate any of these biological parameters with the response to treatment.
Detailed description
There are many mechanisms involved in the antitumor effect of the antibodies including the induction of apoptosis, blocking angiogenesis, blockade of intracellular signaling pathways, and activation of complement leading to lysis of tumor cells. However it appears that the antibody-dependent cellular cytotoxicity (ADCC) is one of the predominant mechanisms of action. It is important to note that in order to obtain a powerful ADCC effect it is necessary the action of the antibody but also the activity of the effector cell, and thus the competence of the immune system of the guest. There are different cellular subpopulations that mediate the ADCC effect. CTL and NK are two of these subpopulations that can be reduced in patients with cancer.
A way to improve the efficiency of the monoclonal antibodies would be to improve the activity of the effector arm of the immune system. A strategy that that has been planed is the utilization of LAK cells. The culture of lymphocytes of peripheral blood with IL-2 activates the subpopulations of killer cells. This population of killer cells activated with cytokines (LAK: lymphokine activated killer) has a high number of NK and CTL cells, both with increased cytotoxic capacity. It has been demonstrated that the immunotherapy with LAK cells might be an effective and sure treatment for patients with follicular lymphoma.
In a murine model it has been demonstrated that LAK cells associated with monoclonal antibodies increase the antitumoral activity when compared to the administration of antibodies alone. In addition, in this model the combination was also superior to the administration of monoclonal antibodies + IL-2 (Schultz et al., 1990). Other investigators have demonstrated similar results. This information supports the idea of the combined therapy consisting in LAK with anti-CD20 antibodies. This therapy can induce a destruction of CD20 positive cells greater than that with the monoclonal antibodies alone. In addition, it has been reported that the administration of systemic IL-2 and LAK cells improves the ADCC in lymphoma patients treated with rituximab. It is a small pilot study, with 10 patients. Seven of them received LAK cells following a programmed way. The safety of the treatment and the promising results demonstrated in this study encourage to investigate in this line.
Since one of the mechanisms of action of the monoclonal antibodies is to promote ADCC , our hypothesis is that the treatment with a suspension of autologous effector lymphocytes expanded ex-vivo with culture should modify the biological effect of the treatment with rituximab in follicular lymphoma patients, with an acceptable safety profile, and probably increasing the efficiency of the monoclonal antibodies. In order to evaluate this hypotesis we propose an open, prospective, historically controlled, phase II clinical study in patients with follicular lymphoma who have achieved a remission after first-line therapy including the anti-CD20 monoclonal antibody rituximab and chemotherapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Autologous effector lymphocytes | Experimental | Biological: Autologous effector lymphocytes expanded ex-vivo |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Patients with histologically-confirmed follicular lymphoma CD20-positive grade 1, 2 ó 3a.
- Patients with aptitude to sign the written informed consent and to express his desire to fulfill all the requirements of the protocol during the period of study.
- Patients not treated before. The induction treatment with rituximab and chemotherapy must be the first line for the patients who are included in the study.
- Patients undergoing maintenance therapy with rituximab every two/three months.
- Ann Arbor stage II, III o IV before receiving the induction treatment with rituximab and chemotherapy.
Key exclusion criteria (16 listed)
- Patients with transformed follicular lymphoma into diffuse large B-cell lymphoma.
- Patients with evidence of follicular lymphoma grade 3b.
- Patients with evidence of primary cutaneous or gastrointestinal follicular lymphoma.
- Patients with evidence of current central nervous system involvement.
- Patients who received previous induction treatment other than rituximab and chemotherapy.
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 |
|---|---|---|
| Autologous effector lymphocytes expanded ex-vivoAlso: LAK, LAK cells, Activated lymphocytesMaintenance therapy with Rituximab every two months is the standard of care for patients with follicular lymphoma after induction therapy. The intervention consists on the administration of autologous effector lymphocytes expanded ex-vivo every two Rituximab administrations. | Biological | Autologous effector lymphocytes |
Primary outcome
Progression free survival (PFS) from the entry in the study.
Time frame: 01/03/2015
The PFS is defined as the time from the entry in the study up to the progression of the disease.
4 secondary outcomes
Event free survival from the entry in the study
Time frame: 01/03/2015
Time to the next anti-lymphoma treatment
Time frame: 01/03/2015
Disease free survival
Time frame: 01/03/2015
Safety
Time frame: 01/01/2012
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Oct 2017.
- Derived from this study: PubMed 26659089Garcia-Munoz R, Lopez-Diaz-de-Cerio A, Feliu J, Panizo A, Giraldo P, Rodriguez-Calvillo M, Grande C, Pena E, Olave M, Panizo C, Inoges S. Follicular lymphoma: in vitro effects of combining lymphokine-activated killer (LAK) cell-induced cytotoxicity and rituximab- and obinutuzumab-dependent cellular cytotoxicity (ADCC) activity. Immunol Res. 2016 Apr;64(2):548-57. doi: 10.1007/s12026-015-8747-9.
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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 2 study testing Autologous effector lymphocytes expanded ex-vivo in people with Follicular Lymphoma and Follicular Non-Hodgkin´s Lymphoma, run by Clinica Universidad de Navarra, Universidad de Navarra at 1 site in Spain.
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 9 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: status not confirmed, as of the sponsor's last update on 24 Oct 2017. 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 Spain. 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?
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?
Progression free survival (PFS) from the entry in the study. (time frame: 01/03/2015). 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 NCT01329354, 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 24 Oct 2017.