| Eligibility |
Inclusion Criteria:
1. Relapsed/refractory CLL in need of treatment according to International Workshop on
Chronic Lymphocytic Leukemia (iwCLL) criteria
In case of a recent previous treatment, patients must have recovered from acute
toxicities and treatment regimen must be stopped within the following time periods
before start of the study treatment in the CLL2-BZAG trial:
- chemotherapy = 28 days
- antibody treatment = 14 days
- kinase inhibitors, BCL2-antagonists or immunomodulatory agents = 3 days
- corticosteroids may be applied until the start of the BZAG-regimen, these have to
be reduced to an equivalent of = 20mg prednisolone per day during treatment
Please note: Patients with a progression during previous treatment with
venetoclax, ibrutinib or another BTK inhibitor, as well as patients with a known
resistance mutation (e.g. BTK-/PLCg2) are excluded from study participation.
However, patients who progressed after termination of treatment with venetoclax,
ibrutinib, other BTK inhibitors and/or obinutuzumab or who stopped treatment due
to intolerance to ibrutinib are eligible for participation.
2. Adequate renal function, as indicated by a creatinine clearance =30ml/min calculated
according to the modified formula of Cockcroft and Gault or directly measured with 24
hr. urine collection
3. Adequate hematologic function as indicated by a neutrophil count = 1.0 x 109/L, a
hemoglobin value =8.0 g/dL and a platelet count = 25 x 109/L, unless directly
attributable to the patient´s CLL (e.g. bone marrow infiltration), in this case,
platelet count should be = 10 × 109/L.
4. Adequate liver function as indicated by a total bilirubin =2x, AST/ALT =2.5x the
institutional ULN value, unless directly attributable to the patient's CLL or to
Gilbert's Syndrome
5. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative,
patients positive for anti-HBc may be included if PCR for Hepatitis B Virus (HBV) DNA
is negative and HBV-DNA PCR is performed every 4 weeks until one year after last
dosage of GA101 (obinutuzumab) or until the last dose of zanubrutinib, whichever
occurs later), negative testing for hepatitis-C RNA and negative HIV test within 6
weeks prior to registration
6. Age = 18 years
7. Eastern Cooperative Oncology Group Performance Status (ECOG) 0 - 2, ECOG 3 is only
permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)
8. Life expectancy = 6 months
9. Ability and willingness to provide written informed consent and to adhere to the study
visit schedule and other protocol requirements
Exclusion Criteria:
1. (Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocytic
leukemia) or central nervous system (CNS) involvement
2. Progression during previous treatment with venetoclax, ibrutinib or another BTK
inhibitor, and/or presence of known mutations associated with resistance to therapy,
e.g. Bruton´s Tyrosine Kinase and Phospholipase C Gamma 2 (PLCg2)
3. Confirmed progressive multifocal leukoencephalopathy (PML)
4. Malignancies other than CLL currently requiring systemic therapies
5. Uncontrolled infection requiring systemic treatment
6. Any comorbidity or organ system impairment rated with a Cumulative Illness Rating
Scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or
any other life-threatening illness, medical condition or organ system dysfunction that
- in the investigator´s opinion - could compromise the patients safety or interfere
with the absorption or metabolism of the study drugs (e.g, inability to swallow
tablets or impaired resorption in the gastrointestinal tract)
7. Significantly increased risk of bleeding according to the investigator´s evaluation,
e.g. due known bleeding diathesis (e.g. von-Willebrandt´s disease or hemophilia),
major surgical procedure = 4 weeks or stroke/intracranial hemorrhage = 6 months.
8. Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with
phenprocoumon (marcumar) or other vitamin K-antagonists
9. Use of investigational agents = 28 days prior to start of study treatment, however,
kinase inhibitors, BCL2-antagonists and antibody treatment are allowed in accordance
with inclusion criterion number 1 (see above).
10. Known hypersensitivity to obinutuzumab (GA101), venetoclax (ABT-199), zanubrutinib
(BGB-3111) or any of the excipients Please note: Patients with a known
hypersensitivity to bendamustine are allowed to participate but will not receive a
debulking with bendamustine
11. Pregnant women and nursing mothers (a negative pregnancy test is required for all
women of childbearing potential within 7 days before start of treatment)
12. Fertile men or women of childbearing potential unless:
- surgically sterile or = 2 years after the onset of menopause, or
- willing to use two methods of reliable contraception including one highly
effective (Pearl Index <1) and one additional effective (barrier) method during
study treatment and for 18 months after end of study treatment.
13. Vaccination with a live vaccine = 28 days prior to registration
14. Legal incapacity
15. Prisoners or subjects who are institutionalized by regulatory or court order
16. Persons who are in dependence to the sponsor or an investigator
|
