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

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Indolent Non-Hodgkin Lymphomas/Chronic Lymphocytic Leukemia

Intervention / Treatment
-----------------
* Biological: Blinatumomab Expanded T-cells (BET)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 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 Exclusion Criteria: 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 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%

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Indolent NHL or CLL patients<br>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)<br>* 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) (starting dose) 3.0 x 109 6.0 x 109 9.0 x 109 12.0 x 109<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | The period of observation is during 14 days after BET infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | +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) | 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). | at +0 (4 hours), +30, +90 and +180 days after infusion |