Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic LeukemiaPhase 1BET2017NCT03823365

Blinatumomab Expanded T-cells (BET) in Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia

A Phase 1 study testing Blinatumomab Expanded T-cells (BET) in people with Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia, run by A.O. Ospedale Papa Giovanni XXIII at 1 site in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia
What is being tested?: Blinatumomab Expanded T-cells (BET)
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 19 participants
Where: 1 siteItaly
Study dates: 17 Dec 2018to Nov 2022
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

1. Male or female patients 18 years or older 2. Confirmed diagnosis of the following CD20+ iNHL or CLL according to (World Health Organization ) WHO criteria:
Follicular NHL
Marginal zone NHL (splenic, extranodal or nodal)
Lymphocytic lymphoma/CLL without del(17p) or TP53 mutations 3. No previous chemotherapy. Previous radiotherapy for localized disease is admitted 4. Requirement for treatment:
For CLL, active disease is defined as meeting at least one of the International Workshop on CLL guidelines (Hallek et al., 2008)
For iNHL, active disease is defined as meeting at least one of the Groupe d'Etudes des Lymphomes Folliculaires (GELF) criteria (Brice et al., 1997) 5. Indication to treatment with either fludarabine, cyclophosphamide and rituximab or bendamustine and rituximab 6. Presence of peripheral blood clone ≥10% of total lymphocytes (with absolute lymphocyte count >800 x106/L) at study entrance 7. Written informed consent prior to any study procedures being performed

Show all 16Show fewer

Additional inclusion criteria to be met at study entry (i.e. before BET infusion):
8. Achieving at least a partial response after three chemo-immunotherapy cycles 9. Absence of any serious therapy-related complications that might affect interpretation of the results of the study or render the subject at high risk from treatment complications 10. Production of adequate BET numbers (counted on CD3+ cells: ≥0.5 x 109) 11. For female patients:
being postmenopausal for at least 1 year before the screening visit, OR
being surgically sterile, OR
if they are of childbearing potential, must agree to practice highly effective method of contraception and one additional effective (barrier) method from the time of signing the informed consent until the end of study. Highly effective method of contraception includes: (i) combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal; (ii) progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable (intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence) OR
must agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject from the time of signing the informed consent until the end of study. [Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.]
For male patients, even if surgically sterilized (i.e., status postvasectomy):
with female partners of childbearing potential: must agree to practice barrier contraception (condom with or without spermicide) from the time of signing the informed consent until the end of study and his female partner must agree to practice method of contraception including one of the following: estrogen and progestogen containing hormonal contraception; inhibition of ovulation: oral, intravaginal, transdermal; progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable (intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion) from the time of signing the informed consent until the end of study.
must agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject from the time of signing the informed consent until the end of study. [Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.]
must agree to refrain from donating sperm

Who cannot join

ECOG (Eastern Cooperative Oncology Group) Performance Status >2
Active central nervous system (CNS) disease
Calculated creatinine clearance (by Cockroft-Gault) of < 50 ml/min or serum creatinine > 1.5x ULN (Upper Limit of Normal )
Concomitant or previous diagnosis of autoimmune hemolytic anemia or thrombocytopenia
Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition requiring the sole hormone replacement are allowed to participate. Psoriasis requiring systemic treatment, or conditions expected to recur at the presence of an external trigger are excluded.
Known infection with human immunodeficiency virus (HIV) or treponema

Show all 10Show fewer

Active hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections
Any suspected or known active infection
History of other diseases, metabolic dysfunctions, physical examination findings, or clinical laboratory findings giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications
Residual CD19+ B cells in BET final cell product ≥0.5%

Trial locations and contacts

1 site in 1 country.

Italy1 site

ASST - Papa Giovanni XXIII
Bergamo, 24127

Other trials in Italy

About this study

Official title: Immune Reconstitution With Blinatumomab Expanded T-cells (BET) After First-line Treatment With Fludarabine-Cyclophosphamide-Rituximab or Bendamustine-Rituximab in CD20+ Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia: a Phase I Study

Non-Hodgkin CD20 + Indolent Lymphoma (iNHL) and Chronic Lymphatic Leukemia (CLL) are the most frequent neoplasms of B lymphocytes. They include various histologies (follicular NHL, marginal zone NHL and Lymphocytic NHL/ CLL) characterized by a chronic course and prolonged survival, but while patients with a limited disease could be cured, those with advanced disease or relapsed after localized radiation therapy are generally considered untreatable through standard treatments. The options for first-line therapy include the use of the FCR scheme, based on Fludarabine, Cyclophosphamide and Rituximab or the BR, with Bendamustine and Rituximab. Despite good results, treatment with these two regimens (FCR or BR) is associated with severe immunosuppression which worsens the immunological dysfunction already present at diagnosis in several patients. It has been shown previously that the adoptive transfer of ex vivo anti-CD3/CD28 co-stimulated autologous T cells can successfully accelerate a robust early recovery of T cells after autologous transplantation in multiple myeloma. These CD3/CD28 expanded T cells cannot however be used in NHLi and CLL due to the presence of contaminating tumor cells in the preparation. Polyclonal T cells can also be expanded in vitro in presence of Blinatumomab and recombinant human IL2 (rhIL2) and have been called BET (Blinatumomab-expanded T cells). They are a product of Advanced Therapeutic Medicinal Product (ATMP) composed of polyclonal CD8 and CD4 T cells that are still functional and devoid of contaminating CD19+ neoplastic cells. Based on these data, it was hypothesized that infusion of BET in patients with iNHL/CLL, after the first treatment line (with FCR or BR), could induce adequate immunological recovery.

Read the detailed description

Indolent non-Hodgkin lymphomas (iNHL) and chronic lymphocytic leukemia (CLL) are among the most frequent B-cell neoplasms. They include different histologies (i.e. follicular NHL, marginal zone NHL and lymphocytic NHL/CLL) characterized by chronic course and prolonged survival. While some patients with limited stage disease may be cured, those presenting with advance stage or relapsing after local radiotherapy are generally considered not curable with standard treatments.
First-line treatment of CLL/LL is currently based on the biologic profile of the disease. Excluding high risk patients harboring the del(17p) and/or TP53 mutations, first line chemoimmunotherapy options includes the use of either fludarabine, cyclophosphamide and rituximab (FCR) or BR. Despite the good results, treatment with FCR or BR regimens is associated with severe immunosuppression that worsens the immune dysfunctions already present at diagnosis in several patients. In the CLL phase III trial, high frequency of grade 3/4 infections was reported in FCR and BR, being observed in 39% and 25% of the patients, respectively. In iNHL, infections have been observed in 37-55% of the patients treated with BR, with grade 3/4 events in 7-12% of the cases.
Blinatumomab-expanded T cells (BET) are an Advanced Therapeutic Medicinal Product (ATMP) composed of autologous polyclonal activated T cells expanded in vitro using blinatumomab and rhIL-2, to be used for somatic cell therapy in an autologous setting. Indeed the investigators have developed a method using blinatumomab and rhIL2 to expand and activate ex vivo the T lymphocytes present in the peripheral blood from CLL and iNHL patients, while at the same time eliminating contaminating CD19+ neoplastic cells. The resulting polyclonal T cells can be used for immuno-reconstitution purposes. The Cell Factory "Centro di Terapia Cellulare G. Lanzani" showed the functionality of BET in a mouse B-cell NHL xenograft model. Upon in vivo inoculation, BET retain functional activity: upon engagement with blinatumomab in vivo, BET were able to efficiently kill the B-cell NHL cells. Importantly, BET did not showed any toxicity in animals, even at high doses and in presence of blinatumomab.
About clinical experience, it has been previously shown that adoptive transfer of ex vivo (anti-CD3/anti-CD28) co-stimulated autologous T cells can successfully accelerate a robust T-cell recovery early after autologous transplant for multiple myeloma. However, the invariable presence of clonal disease in cell product of iNHL/CLL patients hampered this possibility up to now. In contrast BET cell expansion leads to lysis of contaminating neoplastic cells. BET can therefore be expanded from CLL patients peripheral blood in GMP (Good Manufacturing Practice) conditions for adoptive therapy. Starting from only 10 mL of peripheral blood, a mean 5.15x108 CD3+ cells can be expanded in 3 weeks with a rapid clearance of CLL contamination. The resulting blinatumomab-expanded T cells (BET) were polyclonal CD4+ and CD8+ T cells and mostly effector and central memory cells. They showed a normalized expression of the synapse inhibitors CD272 and CD279 compared with starting T cells and were functionally active, showing cytotoxicity against CD19+ targets in presence of Blinatumomab in vitro and in vivo.
On the basis of these data the investigators hypothesize that BET infusion after first-line treatment of iNHL/CLL with either FCR or BR could lead to an adequate immune recovery.

Conditions: Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia
Being tested: Blinatumomab Expanded T-cells (BET)
Medical subject headings: Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Blinatumomab Expanded T-cells (BET)Biological
Two to five days after the last chemotherapy infusion, BET will be administered. An accelerated titration dose escalation design will be used. During dose escalation, up to four dose levels (see table) will be evaluated or until (Maximum Tolerated Dose) MTD is reached.
Dose level BET dose(Counted on CD3+ cells)
1. (starting dose) 3.0 x 109
2. 6.0 x 109
3. 9.0 x 109
4. 12.0 x 109

Study groups in NCT03823365
Study group	Role	What they receive
Indolent NHL or CLL patients	Experimental	Adults diagnosed with indolent non-Hodgkin lymphomas (iNHL) or chronic lymphocytic leukemia (CLL) in need of first line treatment consisting of either FCR or BR as per investigator assessment Receives: Biological: Blinatumomab Expanded T-cells (BET)

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of grade 3 or 4 adverse events (AE) possibly related to therapy
Description and grading of all adverse events will be based on the NCI -CTCAE v4.03 and MedDra code (current version).
Measured: The period of observation is during 14 days after BET infusion

Secondary outcomes (4)

Number of Adverse event (AE) and laboratory abnormalities.
Number, causality and intensity of all adverse events will be evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.03 and MedDRA code (current version).
Measured: From date of study start up to 180 days after BET infusion
Evaluation of Optimal Biological Dose (ODB) of BET cells
OBD of BET will be defined as the absolute number of BET cell that will allow a CD3+ count of > 600 x106/L at +90 days after infusion in at least 70% of the patients.
Measured: +90 days after infusion
Evaluation of general Immune Reconstitution after BET infusion
Absolute numbers of B, T, and NK cells reconstitution and its correlation with BET cell infused and its composition (in terms of T-cell subsets and NK cells)
Measured: at +0 (4 hours), +30, +90 and +180 days after infusion
Evaluation of ex vivo transfer of anti-viral immunity
Ex vivo transfer of anti-viral immunity in terms of tetramer-based quantification of CMV-specific CD8+ T lymphocytes (this will be done only for CMV positive patients for whom CMV specific tetramers stain positive in starting peripheral blood or BET).
Measured: at +0 (4 hours), +30, +90 and +180 days after infusion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

17 Dec 2018Nov 2022

First posted30 Jan 2019
Study start17 Dec 2018
Primary completion11 Nov 2021
Study completionNov 2022 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (31)Papers the sponsor has linked to this study.
Other trials for Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic LeukemiaStudies 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
Model description: CD20+ Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia Patients After First-line Treatment with Fludarabine-Cyclophosphamide-Rituximab or Bendamustine-Rituximab.
Masking: None (open label)
Enrolment: 19 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03823365
Sponsor's protocol ID: EudraCT Nr 2018-000086-36
Acronym: BET2017
Status last verified: Dec 2021
First submitted: 22 Jan 2019
Last updated: 23 Dec 2021
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No

Publications

Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, Marcus RE, Jelliffe A, Vaughan G, Hudson, Linch DC; British National Lymphoma Investigation. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003 Aug 16;362(9383):516-22. doi: 10.1016/s0140-6736(03)14110-4.
PubMed 12932382
Berdeja JG, Hess A, Lucas DM, O'Donnell P, Ambinder RF, Diehl LF, Carter-Brookins D, Newton S, Flinn IW. Systemic interleukin-2 and adoptive transfer of lymphokine-activated killer cells improves antibody-dependent cellular cytotoxicity in patients with relapsed B-cell lymphoma treated with rituximab. Clin Cancer Res. 2007 Apr 15;13(8):2392-9. doi: 10.1158/1078-0432.CCR-06-1860.
PubMed 17438098
Bomberger C, Singh-Jairam M, Rodey G, Guerriero A, Yeager AM, Fleming WH, Holland HK, Waller EK. Lymphoid reconstitution after autologous PBSC transplantation with FACS-sorted CD34+ hematopoietic progenitors. Blood. 1998 Apr 1;91(7):2588-600.
PubMed 9516161
Brice P, Bastion Y, Lepage E, Brousse N, Haioun C, Moreau P, Straetmans N, Tilly H, Tabah I, Solal-Celigny P. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 1997 Mar;15(3):1110-7. doi: 10.1200/JCO.1997.15.3.1110.
PubMed 9060552
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.
PubMed 25113753
Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst. 1999 May 19;91(10):861-8. doi: 10.1093/jnci/91.10.861.
PubMed 10340906
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. doi: 10.1159/000180580.
PubMed 1244564
Darwish M, Bond M, Hellriegel E, Robertson P Jr, Chovan JP. Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. Cancer Chemother Pharmacol. 2015 Jun;75(6):1143-54. doi: 10.1007/s00280-015-2727-6. Epub 2015 Apr 1.
PubMed 25829094
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013 Apr 18;368(16):1509-1518. doi: 10.1056/NEJMoa1215134. Epub 2013 Mar 25.
PubMed 23527958
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. doi: 10.1182/blood-2007-06-093906. Epub 2008 Jan 23.
PubMed 18216293
Introna M, Borleri G, Conti E, Franceschetti M, Barbui AM, Broady R, Dander E, Gaipa G, D'Amico G, Biagi E, Parma M, Pogliani EM, Spinelli O, Baronciani D, Grassi A, Golay J, Barbui T, Biondi A, Rambaldi A. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica. 2007 Jul;92(7):952-9. doi: 10.3324/haematol.11132.
PubMed 17606446
Introna M, Pievani A, Borleri G, Capelli C, Algarotti A, Mico C, Grassi A, Oldani E, Golay J, Rambaldi A. Feasibility and safety of adoptive immunotherapy with CIK cells after cord blood transplantation. Biol Blood Marrow Transplant. 2010 Nov;16(11):1603-7. doi: 10.1016/j.bbmt.2010.05.015. Epub 2010 Jun 1.
PubMed 20685246
Kalamasz D, Long SA, Taniguchi R, Buckner JH, Berenson RJ, Bonyhadi M. Optimization of human T-cell expansion ex vivo using magnetic beads conjugated with anti-CD3 and Anti-CD28 antibodies. J Immunother. 2004 Sep-Oct;27(5):405-18. doi: 10.1097/00002371-200409000-00010.
PubMed 15314550
Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012 Mar 22;119(12):2709-20. doi: 10.1182/blood-2011-10-384388. Epub 2011 Dec 8.
PubMed 22160384
Levine BL, Bernstein WB, Connors M, Craighead N, Lindsten T, Thompson CB, June CH. Effects of CD28 costimulation on long-term proliferation of CD4+ T cells in the absence of exogenous feeder cells. J Immunol. 1997 Dec 15;159(12):5921-30.
PubMed 9550389

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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All Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia trials

Study at a glance

From the registry record, last updated by the sponsor on 23 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Immune Reconstitution With Blinatumomab Expanded T-cells (BET) After First-line Treatment With Fludarabine-Cyclophosphamide-Rituximab or Bendamustine-Rituximab in CD20+ Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia: a Phase I Study
ClinicalTrials.gov ID: NCT03823365
Acronym / sponsor ID: BET2017 / EudraCT Nr 2018-000086-36
Conditions: Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia
Phase: Phase 1
Study type: Interventional
Recruitment status: Unknown status
Enrolment: 19 participants (actual)
Lead sponsor: A.O. Ospedale Papa Giovanni XXIIIUniversity, hospital or other
Study start: 17 Dec 2018 (actual)
Primary completion: 11 Nov 2021 (actual)
Study completion: Nov 2022 (estimated)
First posted: 30 Jan 2019 (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.

Detailed description

Indolent non-Hodgkin lymphomas (iNHL) and chronic lymphocytic leukemia (CLL) are among the most frequent B-cell neoplasms. They include different histologies (i.e. follicular NHL, marginal zone NHL and lymphocytic NHL/CLL) characterized by chronic course and prolonged survival. While some patients with limited stage disease may be cured, those presenting with advance stage or relapsing after local radiotherapy are generally considered not curable with standard treatments.
First-line treatment of CLL/LL is currently based on the biologic profile of the disease. Excluding high risk patients harboring the del(17p) and/or TP53 mutations, first line chemoimmunotherapy options includes the use of either fludarabine, cyclophosphamide and rituximab (FCR) or BR. Despite the good results, treatment with FCR or BR regimens is associated with severe immunosuppression that worsens the immune dysfunctions already present at diagnosis in several patients. In the CLL phase III trial, high frequency of grade 3/4 infections was reported in FCR and BR, being observed in 39% and 25% of the patients, respectively. In iNHL, infections have been observed in 37-55% of the patients treated with BR, with grade 3/4 events in 7-12% of the cases.
Blinatumomab-expanded T cells (BET) are an Advanced Therapeutic Medicinal Product (ATMP) composed of autologous polyclonal activated T cells expanded in vitro using blinatumomab and rhIL-2, to be used for somatic cell therapy in an autologous setting. Indeed the investigators have developed a method using blinatumomab and rhIL2 to expand and activate ex vivo the T lymphocytes present in the peripheral blood from CLL and iNHL patients, while at the same time eliminating contaminating CD19+ neoplastic cells. The resulting polyclonal T cells can be used for immuno-reconstitution purposes. The Cell Factory "Centro di Terapia Cellulare G. Lanzani" showed the functionality of BET in a mouse B-cell NHL xenograft model. Upon in vivo inoculation, BET retain functional activity: upon engagement with blinatumomab in vivo, BET were able to efficiently kill the B-cell NHL cells. Importantly, BET did not showed any toxicity in animals, even at high doses and in presence of blinatumomab.
About clinical experience, it has been previously shown that adoptive transfer of ex vivo (anti-CD3/anti-CD28) co-stimulated autologous T cells can successfully accelerate a robust T-cell recovery early after autologous transplant for multiple myeloma. However, the invariable presence of clonal disease in cell product of iNHL/CLL patients hampered this possibility up to now. In contrast BET cell expansion leads to lysis of contaminating neoplastic cells. BET can therefore be expanded from CLL patients peripheral blood in GMP (Good Manufacturing Practice) conditions for adoptive therapy. Starting from only 10 mL of peripheral blood, a mean 5.15x108 CD3+ cells can be expanded in 3 weeks with a rapid clearance of CLL contamination. The resulting blinatumomab-expanded T cells (BET) were polyclonal CD4+ and CD8+ T cells and mostly effector and central memory cells. They showed a normalized expression of the synapse inhibitors CD272 and CD279 compared with starting T cells and were functionally active, showing cytotoxicity against CD19+ targets in presence of Blinatumomab in vitro and in vivo.
On the basis of these data the investigators hypothesize that BET infusion after first-line treatment of iNHL/CLL with either FCR or BR could lead to an adequate immune recovery.

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1
Model description: CD20+ Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia Patients After First-line Treatment with Fludarabine-Cyclophosphamide-Rituximab or Bendamustine-Rituximab.

Arm	Type	Receives
Indolent NHL or CLL patients	Experimental	Biological: Blinatumomab Expanded T-cells (BET)Adults diagnosed with indolent non-Hodgkin lymphomas (iNHL) or chronic lymphocytic leukemia (CLL) in need of first line treatment consisting of either FCR or BR as per investigator assessment

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (16 listed)

1. Male or female patients 18 years or older 2. Confirmed diagnosis of the following CD20+ iNHL or CLL according to (World Health Organization ) WHO criteria:
8. Achieving at least a partial response after three chemo-immunotherapy cycles 9. Absence of any serious therapy-related complications that might affect interpretation of the results of the study or render the subject at high risk from treatment complications 10. Production of adequate BET numbers (counted on CD3+ cells: ≥0.5 x 109) 11. For female patients:
being postmenopausal for at least 1 year before the screening visit, OR
being surgically sterile, OR
if they are of childbearing potential, must agree to practice highly effective method of contraception and one additional effective (barrier) method from the time of signing the informed consent until the end of study. Highly effective method of contraception includes: (i) combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal; (ii) progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable (intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence) OR

Key exclusion criteria (10 listed)

ECOG (Eastern Cooperative Oncology Group) Performance Status >2
Active central nervous system (CNS) disease
Calculated creatinine clearance (by Cockroft-Gault) of < 50 ml/min or serum creatinine > 1.5x ULN (Upper Limit of Normal )
Concomitant or previous diagnosis of autoimmune hemolytic anemia or thrombocytopenia
Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition requiring the sole hormone replacement are allowed to participate. Psoriasis requiring systemic treatment, or conditions expected to recur at the presence of an external trigger are excluded.

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
Blinatumomab Expanded T-cells (BET)Two to five days after the last chemotherapy infusion, BET will be administered. An accelerated titration dose escalation design will be used. During dose escalation, up to four dose levels (see table) will be evaluated or until (Maximum Tolerated Dose) MTD is reached. Dose level BET dose(Counted on CD3+ cells) 1. (starting dose) 3.0 x 109 2. 6.0 x 109 3. 9.0 x 109 4. 12.0 x 109	Biological	Indolent NHL or CLL patients

Primary outcome

Number of grade 3 or 4 adverse events (AE) possibly related to therapy
Time frame: The period of observation is during 14 days after BET infusion
Description and grading of all adverse events will be based on the NCI -CTCAE v4.03 and MedDra code (current version).

4 secondary outcomes

Number of Adverse event (AE) and laboratory abnormalities.
Time frame: From date of study start up to 180 days after BET infusion
Evaluation of Optimal Biological Dose (ODB) of BET cells
Time frame: +90 days after infusion
Evaluation of general Immune Reconstitution after BET infusion
Time frame: at +0 (4 hours), +30, +90 and +180 days after infusion
Evaluation of ex vivo transfer of anti-viral immunity
Time frame: at +0 (4 hours), +30, +90 and +180 days after infusion

Results and safety

Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 23 Dec 2021.
Background: PubMed 12932382Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, Marcus RE, Jelliffe A, Vaughan G, Hudson, Linch DC; British National Lymphoma Investigation. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003 Aug 16;362(9383):516-22. doi: 10.1016/s0140-6736(03)14110-4.
Background: PubMed 17438098Berdeja JG, Hess A, Lucas DM, O'Donnell P, Ambinder RF, Diehl LF, Carter-Brookins D, Newton S, Flinn IW. Systemic interleukin-2 and adoptive transfer of lymphokine-activated killer cells improves antibody-dependent cellular cytotoxicity in patients with relapsed B-cell lymphoma treated with rituximab. Clin Cancer Res. 2007 Apr 15;13(8):2392-9. doi: 10.1158/1078-0432.CCR-06-1860.
Background: PubMed 9516161Bomberger C, Singh-Jairam M, Rodey G, Guerriero A, Yeager AM, Fleming WH, Holland HK, Waller EK. Lymphoid reconstitution after autologous PBSC transplantation with FACS-sorted CD34+ hematopoietic progenitors. Blood. 1998 Apr 1;91(7):2588-600.
Background: PubMed 9060552Brice P, Bastion Y, Lepage E, Brousse N, Haioun C, Moreau P, Straetmans N, Tilly H, Tabah I, Solal-Celigny P. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 1997 Mar;15(3):1110-7. doi: 10.1200/JCO.1997.15.3.1110.
Background: PubMed 25113753Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.
Background: PubMed 10340906Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst. 1999 May 19;91(10):861-8. doi: 10.1093/jnci/91.10.861.
Background: PubMed 1244564Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. doi: 10.1159/000180580.
Background: PubMed 25829094Darwish M, Bond M, Hellriegel E, Robertson P Jr, Chovan JP. Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. Cancer Chemother Pharmacol. 2015 Jun;75(6):1143-54. doi: 10.1007/s00280-015-2727-6. Epub 2015 Apr 1.
Background: PubMed 23527958Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013 Apr 18;368(16):1509-1518. doi: 10.1056/NEJMoa1215134. Epub 2013 Mar 25.
Background: PubMed 18216293Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. doi: 10.1182/blood-2007-06-093906. Epub 2008 Jan 23.
Background: PubMed 17606446Introna M, Borleri G, Conti E, Franceschetti M, Barbui AM, Broady R, Dander E, Gaipa G, D'Amico G, Biagi E, Parma M, Pogliani EM, Spinelli O, Baronciani D, Grassi A, Golay J, Barbui T, Biondi A, Rambaldi A. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica. 2007 Jul;92(7):952-9. doi: 10.3324/haematol.11132.
Background: PubMed 20685246Introna M, Pievani A, Borleri G, Capelli C, Algarotti A, Mico C, Grassi A, Oldani E, Golay J, Rambaldi A. Feasibility and safety of adoptive immunotherapy with CIK cells after cord blood transplantation. Biol Blood Marrow Transplant. 2010 Nov;16(11):1603-7. doi: 10.1016/j.bbmt.2010.05.015. Epub 2010 Jun 1.

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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.

Alessandro Rambaldi, MD principal investigator

ASST - Papa Giovanni XXIII

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 Blinatumomab Expanded T-cells (BET) in people with Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia, run by A.O. Ospedale Papa Giovanni XXIII at 1 site in Italy.

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 16 inclusion and 10 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 23 Dec 2021. 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 Italy. 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?

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?

Number of grade 3 or 4 adverse events (AE) possibly related to therapy (time frame: The period of observation is during 14 days after BET infusion). 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 NCT03823365, which also lists 31 linked publications.

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 23 Dec 2021.