Patients with relapsed/refractory CLL requiring treatment MedDRA version: 21.1 Level: PT Classification code 10008958 Term: Chronic lymphocytic leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Bendamustine
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: BENDAMUSTINE HYDROCHLORIDE
CAS Number: 3543-75-7
Concentration unit: mg/ml milligr
Sponsors
Universität zu Köln B.1.2
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Relapsed/refractory CLL in need of treatment according to iwCLL criteria3 In case of a recent previous treatment, patients must have recovered from acute toxicities and treatment regi-men 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 immuno-modulatory 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 inhibi-tor, 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 in-tolerance 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 neutro-phil count = 1.0 x 109/L, a hemoglobin value =8.0 g/dL and a platelet count = 25 x 109/L, unless directly attributa-ble 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 di-rectly attributable to the patient’s CLL or to Gilbert’s Syn-drome 5. Negative serological testing for hepatitis B (HBsAg nega-tive and anti-HBc negative, patients positive for anti-HBc may be included if PCR for 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), nega-tive testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration 6. Age = 18 years 7. ECOG 0 to 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 con-sent and to adhere to the study visit schedule and other protocol requirements Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 15 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 25
Exclusion criteria
Exclusion criteria: 1. (Suspicion of) transformation of CLL (i.e. Richter’s trans-formation, 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 CIRS (cumulative illness rating scale) score of 4, exclud-ing 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, inabil-ity to swallow tablets or impaired resorption in the gastro-intestinal tract) 7. Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diath-esis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure = 4 weeks or stroke/intracranial hemor-rhage = 6 months. 8. Requirement of therapy with strong CYP3A4 inhibi-tors/inducers or anticoagulant with phenprocoumon (mar-cumar) 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 ac-cordance with inclusion criterion number 1 (see above). 10. Known hypersensitivity to obinutuzumab (GA101), ve-netoclax (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 re-ceive a debulking with bendamustine 11. Pregnant women and nursing mothers (a negative preg-nancy test is required for all women of childbearing po-tential 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 contracep-tion 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 registra-tion 14. Legal incapacity 15. Prisoners or subjects who are institutionalized by regula-tory or court order 16. Persons who are in dependence to the sponsor or an in-vestigator
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to evaluate the efficacy of a sequential regimen of two cycles of bendamustine, followed by a combination therapy of GA101 (obinutuzumab), zanubrutinib (BGB-3111) and ABT-199 (venetoclax) in patients with relapsed/refractory CLL.;Secondary Objective: The secondary objective is to evaluate the safety of a sequential regimen of two cycles of bendamustine, followed by a combination therapy of GA101 (obinutuzumab), zanubrutinib (BGB-3111) and ABT-199 (venetoclax) in patients with relapsed/refractory CLL.;Primary end point(s): Negativity rate of minimal residual disease (MRD) in peripher-al blood (PB) measured by multi-color flow cytometry at final restaging (RE) at the end of induction treatment (12 weeks af-ter the start of the last induction cycle);Timepoint(s) of evaluation of this end point: The primary endpoint can be analyzed as soon as all enrolled patients who did not discontinue prematurely have achieved the landmark final restaging 12 weeks after the start of the last cycle of induction treat-ment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Overall response rate (ORR) according to iwCLL criteria at RE 12 weeks after the start of the last cycle of induction therapy including all patients achieving: - a complete response (CR), - CR with incomplete recovery of the bone marrow (CRi), or - a partial response (PR) - CR/CRi rate at RE 12 weeks after the start of the last cycle of induction therapy - Safety parameters: Type, frequency, severity, and relation-ship to study treatment of - adverse events (AE), - serious adverse events (SAE) and - adverse events of particular/special interest (AEPI/AESI) - MRD in PB measured by 4-color flow cytometry to guide the duration of maintenance therapy at: - RE 12 weeks after the start of the last cycle of induc-tion therapy in all patients responding to study treat-ment and - every 12 weeks (= approx. 3 months) during the maintenance phase - every 24 weeks (= approx. 6 months) during the fol-low-up and MRD in PB measured by 4-color flow cytometry for the assessment of the kinetics of response to the different treatment phases at: - screening/baseline - staging after debulking (if applicable) - before start with zanubrutinib (cycle 2, d1) - before start with venetoclax (cycle 3, d1) - interim staging (after 3 induction cycles) - initial response assessment (after 6 induction cycles) - MRD in bone marrow measured by 4-color flow cytometry op-tionally in patients with (clin.) CR/CRi (or PR almost fulfilling CR criteria, e.g. with residual splenomegaly) 12 weeks after achievement of MRD negativity in PB - Best response rate (BRR) until 6 months after RE - ORR after debulking - ORR after end of maintenance treatment - Progression-free survival (PFS) - Event-free survival (EFS) - Overall survival (OS) - Duration of response in patients with - a complete response (CR), - a CR with incomplete recovery of the bone marrow (CRi), - a partial response (PR) - Treatment-free survival (TFS) and time to next CLL treatment (TTNT) Exploratory endpoints | — |
Countries
Germany
Contacts
Public ContactInformation Desk
German CLL Study Group
Outcome results
None listed