Blinatumomab Expanded T-cells (BET) in Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia (BET2017)
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|ClinicalTrials.gov Identifier: NCT03823365|
Recruitment Status : Recruiting
First Posted : January 30, 2019
Last Update Posted : January 30, 2019
|Condition or disease||Intervention/treatment||Phase|
|Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia||Biological: Blinatumomab Expanded T-cells (BET)||Phase 1|
- 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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||13 participants|
|Intervention Model:||Single Group Assignment|
|Intervention 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)|
|Masking Description:||This study is a phase I open-label, single center study. The patient population will consist of 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. Chemotherapy treatment will consist of a minimum of 4 to a maximum of 6 cycles of standard FCR or BR.Patients will be enrolled in the study after the last planned cycle of chemo-immunotherapy and, if eligibility criteria are met, BET dose level will be assigned.|
|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|
|Actual Study Start Date :||December 17, 2018|
|Estimated Primary Completion Date :||August 2021|
|Estimated Study Completion Date :||November 2021|
Experimental: Indolent NHL or CLL patients
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
Biological: 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)
- 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).
- Number of Adverse event (AE) and laboratory abnormalities. [ Time Frame: From date of study start up to 180 days after BET infusion ]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).
- Evaluation of Optimal Biological Dose (ODB) of BET cells [ Time Frame: +90 days after infusion ]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.
- Evaluation of general Immune Reconstitution after BET infusion [ Time Frame: at +0 (4 hours), +30, +90 and +180 days after 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)
- Evaluation of ex vivo transfer of anti-viral immunity [ Time Frame: at +0 (4 hours), +30, +90 and +180 days after infusion ]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).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03823365
|Contact: Alessandro Rambaldi, MD||+39 035 2673683 ext firstname.lastname@example.org|
|Contact: Giuseppe Gritti, MD||+39 035 2673679 ext email@example.com|
|ASST - Papa Giovanni XXIII||Recruiting|
|Bergamo, Italy, 24127|
|Contact: Alessandro Rambaldi, MD +39 035 2673683 ext 3683 firstname.lastname@example.org|
|Contact: Giuseppe Gritti, MD +39 035 2673679 ext 3679 email@example.com|
|Sub-Investigator: Federico Lussana, MD|
|Sub-Investigator: Martino Introna, MD|
|Sub-Investigator: Josee Golay, Biol. Sc|
|Principal Investigator:||Alessandro Rambaldi, MD||ASST - Papa Giovanni XXIII|