| Eligibility |
Inclusion Criteria:
1. Refractory/relapsed B-NHL (including malignant transformation like Richter's
transformation) with no available approved standard therapy. Including, but not
restricted to:
1. Diffuse large B cell lymphoma (DLBCL): relapsed/refractory disease after ASCT or
ineligible for ASCT after first-line therapy; transformation from CLL, SLL or FL
allowed
2. Follicular lymphoma: at least 2 prior regimens and progression <2 years after
most recent line of therapy
3. Mantle cell lymphoma: beyond 1st CR with relapsed disease, progressive disease
during first-line rituximab chemotherapy, or persistent disease after first-line
rituximab-chemotherapy and not eligible or appropriate for conventional therapy,
ASCT or relapsed after prior autologous SCT, prior therapies including ibrutinib
if not contraindicated
4. CLL and SLL: after at least two lines of treatment including btk inhibitor
ibrutinib and bcl2 inhibitor venetoclax (if not contraindicated), patients must
have been refractory to at least one of the substances
Patients with criteria 1b-d will only be eligible for Part I, dose cohort 1.
2. Patients in cohort 1a must have histologically confirmed DLBCL and associated subtypes
with relapse or refractory disease after first line chemo-immunotherapy and be
ineligible for HSCT
3. Histologically confirmed DLBCL and associated subtypes, defined by WHO 2016
classification:
- DLBCL not otherwise specified (NOS)
- High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with
DLBCL histology (DHL/THL) and FL3B
- Aggressive B-cell lymphoma
- T-cell/histocyte rich B-cell lymphoma
- Primary mediastinal B-cell lymphoma
- EBV+ DLBCL
- Transformed lymphoma (e.g. transformed follicular or marginal zone lymphoma)
4. First line chemo-immunotherapy is defined as therapy containing the combination of
CD20 targeted immunotherapy and cytotoxic chemotherapy.
5. Chemotherapy-refractory disease is defined as one or more of the following:
- No response to first line of therapy
- PD as best response to first line therapy regimen
- SD as best response after 4 cycles of first line therapy
- Disease progression or relapsed =12 months of first line therapy (must have
biopsy proven recurrence in relapsed individuals)
6. Ineligibility for HSCT is defined as having ONE of the following criteria:
- Age based on country-specific definition
- Impaired pulmonary function (DLCO or FEV1 =60%)
- Impaired cardiac function (LVEF <50%)
- Impaired renal function (CrCl <60 mL/min)
- Impaired hepatic function (AST/ALT >3 x ULN, bilirubin >1.5 x ULN or patient's
baseline)
In addition, all patients must fulfil the following criteria:
7. Age =18 years
8. Measurable disease according to Lugano criteria
9. CD19 or CD20 tumor expression is not required after first line chemo-immunotherapy.
1. Must have archival tissue available, if received CD19 targeted therapy or CD20
antibody, archival tissue must have been obtained subsequent to that therapy
2. Must have at least 10 unstained slides of tissue available
3. If archival tissue is not available, must be willing to undergo attempted repeat
biopsy and fine needle Aspiration
10. If has history of CNS disease, then must have:
1. No signs or symptoms of CNS disease
2. No active disease on magnetic resonance imaging (MRI)
3. Absence of large cell lymphoma in cerebral spinal fluid (CSF) on cytospin
preparation and flow cytometry, regardless of the number of white blood cells
11. If has history of cerebral vascular accident (CVA):
1. The CVA event must be >12 months prior to leukapheresis
2. Any neurological deficits must be stable
12. Estimated life expectancy of >3 months other than primary disease
13. No childbearing potential (i.e. postmenopausal, absence of menstrual bleeding for at
least 1 year), hysterectomy, bilateral ovariectomy or tubal section/ligation) or
negative pregnancy test at screening and before chemotherapy in women of childbearing
potential. Sexually active female patients of childbearing potential should use one of
the following highly effective methods of contraception (Pearl index <1%): hormonal
contraceptives (oral, injected, implanted, transdermal), intrauterine devices or
systems (e.g. hormonal and non-hormonal IUD), or vasectomized sexual partner for at
least 1 month before the trial start, during the trial and in the 6 months following
dosing. Male patients, unless surgically sterile (meaning at least two consecutive
analyses following vasectomy demonstrate absence of sperms in the ejaculate), must be
using two acceptable methods for contraception (e.g. spermicide and condom) during the
trial and refrain from fathering a child throughout the trial and for up to 12 months
after dosing
14. Signed and dated informed consent before conduct of any trial-specific procedure
Exclusion Criteria:
1. Eastern Cooperative Oncology Group (ECOG) performance status >2
2. Absolute neutrophil count (ANC) <1,000/µL
3. Platelet count <50,000/µL
4. Absolute lymphocyte count <100/µL
5. Presence of leukemia/lymphoma cells in peripheral blood
6. Primary CNS lymphoma
7. Unable to give informed consent
8. Known history of infection with human immunodeficiency virus (HIV) or active infection
with hepatitis B (HGsAg positive)
9. Known history of infection with hepatitis C virus unless treated and confirmed to be
polymerase chain reaction (PCR) negative
10. Known history or presence of seizure activities or on active anti-seizure medications
within the previous 12 months
11. Known history of CVA within prior 12 months
12. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic
neuritis or other immunologic or inflammatory disease
13. Presence of CNS disease that, in the judgment of the investigator, may impair the
ability to evaluate neurotoxicity
14. Active systemic fungal, viral or bacterial infection
15. Clinical heart failure with New York Heart Association class =2 or LVEF <30%
16. Resting oxygen saturation <90% on room air
17. Liver dysfunction as indicated by total bilirubin, AST and/or ALT >5 x institutional
ULN, unless directly attributable to patient's tumor
18. CrCl <30 mL/min calculated according to the modified formula of Cockcroft and Gault or
by direct urine collection
19. Pregnant or breast-feeding woman
20. Active secondary malignancy requiring treatment
21. Medical condition requiring prolonged use of systemic corticosteroids >10 mg/day
22. Concurrent radiotherapy (allow up to time of leukapheresis)
23. Baseline dementia that would interfere with therapy or monitoring, determined using
mini-mental status exam at baseline
24. History of severe immediate hypersensitivity reaction against any drug or its
ingredients/impurities that is scheduled to be given during trial participation e.g.
as part of the mandatory lymphodepletion protocol, premedication for infusion, or
rescue medication/salvage therapies for treatment related toxicities
25. Patients in which such medication (see exclusion criterion 24) is contraindicated for
other reasons than hypersensitivity (e.g. live vaccines and fludarabine)
26. Refusal to participate in CAR-T long-term follow-up (LTFU).
27. Refusal to undergo core needle biopsy or fine needle aspiration of tumor on day 2-5
after MB-CART infusion and at time of disease progression and relapse
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