Sequential Regimen of Bendamustin-Debulking Followed by Obinutuzumab, Acalabrutinib and Venetoclax in Patients With Relapsed/Refractory CLL

Chronic Lymphoid Leukemia Clinical Trial

— CLL2-BAAG  

Official title:

A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by GA101 (Obinutuzumab), Acalabrutinib (ACP-196) and ABT-199 (Venetoclax) in Patients With Relapsed/Refractory CLL (CLL2-BAAG Protocol)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03787264
• Other study ID #: CLL2-BAAG
• Status: Completed
• Phase: Phase 2
• Start date: January 14, 2019
• Est. completion date: September 26, 2023

Study information

• Verified date: November 2023
• Source: German CLL Study Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

CLL2-BAAG is a prospective, open-label, multicenter phase-II trial to evaluate the efficacy and safety of a sequential regimen of debulking with bendamustine followed by induction and maintenance with GA101 (obinutuzumab), acalabrutinib (ACP-196) and venetoclax (ABT-199) in patients with relapsed/refractory CLL.

Description:

In the CLL2-BAAG trial will be included a total of 46 patients with relapsed or refractory CLL in need of treatment.This trial will evaluate a debulking with two cycles bendamustine (only for patients with a higher tumor load), followed by an induction and a maintenance treatment with obinutuzumab, acalabrutinib and venetoclax in patients with re-lapsed/refractory CLL. The duration of maintenance treatment is depending on MRD levels. This trial combines one old (chemotherapy) and three novel, synergistic (antibody, BTK-inhibitor and Bcl-2 antagonist) principles of action in order to achieve deep and long lasting remissions with a short duration of treatment. Additionally, this trial has an extensive accompanying scientific program aiming at a better understanding of the kinetics of response and clonal evolution of CLL.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: September 26, 2023
• Est. primary completion date: February 11, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Relapsed/refractory CLL in need of treatment according to iwCLL (international workshop on CLL) 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-BAAG 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 BAAG-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 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 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 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)), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration

6. Age = 18 years

7. ECOG (Eastern Cooperative Oncology Group) performance status 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 proto-col requirements

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. Bru-ton´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 system1 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), acalabrutinib (ACP-196) 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 preg-nancy 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 regula-tory or court order

16. Persons who are in dependence to the sponsor or an investigator

Related Conditions & MeSH terms

• Chronic Lymphoid Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Bendamustine
Debulking: Cycles 1-2: d1+2 - 70mg/m² i.v.

Biological:
• Obinutuzumab
Induction: Cycle 1: d1 - 100 mg, d1 (or d2) - 900 mg, d8 + d15 - 1000 mg i.v.; Cycle 2 - 6: 1000 mg, d1 i.v. Maintenance: Cycle 1 - 8: 1000 mg, d1 i.v.
• Acalabrutinib
Induction: Cycle 1: --; Cycles 2 - 6: d1-28: 2 x 100mg p.o. Maintenance: Cycle 1 - 8: d1-84: 2 x 100mg p.o.
• Venetoclax
Induction: Cycles 1 + 2: --; Cycle 3: d1-7: 20mg, d8-14: 50mg, d15-21: 100mg, d22-28: 200mg p.o.; Cycle 4 - 6: d1-28: 400 mg p.o. Maintenance: Cycle 1 - 8: d1-84: 400 mg p.o.

Locations

Country	Name	City	State
Germany	Gemeinschaftspraxis Hämatologie Onkologie	Dresden
Germany	Gemeinschaftspraxis Mohm/Prange-Krex	Dresden
Germany	Universitatsklinik Carl Gustav Carus	Dresden
Germany	Helios Klinikum Erfurt	Erfurt
Germany	Universitaetsklinikum Heidelberg	Heidelberg
Germany	Universitaetsklinikum Jena	Jena
Germany	Praxis fuer Haematologie und Onkologie	Koblenz
Germany	Universitätsklinik Köln	Köln
Germany	Gemeinschaftspraxis Haemato/ Onkologie Lebach	Lebach
Germany	Klinikum Leverkusen GmbH	Leverkusen
Germany	Ludwig-Maximilians-Universitaet Muenchen	München
Germany	Krankenhaus Muenchen-Schwabing	Munich
Germany	Praxis Dr. Uhlig	Naunhof
Germany	Universitätsklinik Rostock	Rostock
Germany	ZAHO-Rheinland	Siegburg
Germany	Universitaetsklinik Tuebingen	Tübingen
Germany	Universitätsklinikum Ulm	Ulm

Sponsors (1)

Lead Sponsor	Collaborator
German CLL Study Group

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by 4-color flow cytometry	MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed [0.01%], i.e. < 10-4. The MRD negativity rate is defined as the proportion of patients having achieved MRD negativity based on the full analysis set (FAS).	At final restaging (RE): 12 weeks after the start of the last induction cycle
Secondary	Overall response rate (ORR)	Proportion of patients having achieved a complete response (CR), a CR with incomplete recovery of the bone marrow (CRi), or a partial response(PR) as best response.	At final restaging (RE): 12 weeks after the start of the last induction cycle
Secondary	CR / CRi rate	Proportion of patients having achieved a CR or CRi as best response	At final restaging (RE): 12 weeks after the start of the last induction cycle
Secondary	MRD in PB measured by 4-color flow cytometry at different times: At screening, after debulking, 4-weekly during induction, at initial response assessment (after 6 induction cycles), at RE, every 12 weeks during maintenance and follow up.	MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed [0.01%], i.e. < 10-4. MRD values will be categorized into negative (<10-4) and positive (=10-4)	From date of screening until the end of follow-up, up to 40 month.
Secondary	Safety: Adverse events (AE), serious adverse events (SAE) and adverse events of particular interest (AEPI)	Type, frequency, and severity of AEs, SAEs and AESIs and their relationship to study treatment.	up to 40 months after first dose of study drug

External Links

•   Click here for more information about this study: CLL2-BAAG (German CLL Study Group)