Evaluation of a treatment with bendamustine, followed by obinutuzumab, zanubrutinib and venetoclax in patients with relapsed chronic lymphocytic leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Of Cologne

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Sep 2020 → ongoing

Decision date (initial)

2024-06-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2022-502201-16-00

EudraCT number

2018-003270-27

ClinicalTrials.gov

NCT04515238

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

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 chronic lymphocytic leukemia

Secondary objectives 1

1. 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

Conditions and MedDRA coding

Relapsed/refractory chronic lymphocytic leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Relapsed/refractory CLL in need of treatment according to 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 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 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 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 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 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), negative 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 consent and to adhere to the study visit schedule and other protocol requirements

Exclusion criteria 16

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 CIRS (cumulative illness rating scale) 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 gastroin-testinal tract)
7. Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathe-sis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure ≤ 4 weeks or stroke/intracranial hem-orrhage ≤ 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 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 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 registra-tion
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 in-vestigator

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 after the start of the last induction cycle)

Secondary endpoints 14

1. Overall response rate (ORR) according to iwCLL criteria at RE 12 weeks after the start of the last cycle of induction ther-apy including all patients achieving: - a complete response (CR), - CR with incomplete recovery of the bone marrow (CRi), or - a partial response (PR)
2. CR/CRi rate at RE 12 weeks after the start of the last cycle of induction therapy
3. 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)
4. 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
5. and MRD in PB measured by 4-color flow cytometry for the assessment of the kinetics of response to the different treat-ment 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)
6. 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
7. Best response rate (BRR) until 6 months after RE
8. ORR after debulking
9. ORR after end of maintenance treatment
10. Progression-free survival (PFS)
11. Event-free survival (EFS)
12. Overall survival (OS)
13. Duration of response in patients with - a complete response (CR), - a CR with incomplete recovery of the bone marrow (CRi), - a partial response (PR)
14. Treatment-free survival (TFS) and time to next CLL treatment (TTNT)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Of Cologne

Sponsor organisation

University Of Cologne

Address

Albertus-Magnus-Platz 1

City

Cologne

Postcode

50923

Country

Germany

Scientific contact point

Organisation

University Of Cologne

Contact name

Paula Cramer

Public contact point

Organisation

University Of Cologne

Contact name

Paula Cramer

Third parties 9

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications