Sequential Regimen of Bendamustin [B] Followed by GA101 and Ibrutinib [I] in CLL Patients

Conditions

Chronic Lymphocytic Leucemia

Keywords

CLL

Brief summary

A prospective, open-label, multicenter Phase-II trial to evaluate the efficacy and safety of a sequential regimen of Bendamustine followed by GA101 and Ibrutinib followed by Ibrutinib and GA101 maintenance in CLL patients.

Detailed description

In the CLL2-BIG trial an allcomer CLL population with indication for treatment will be included. Patient will receive 2 cycles of debulking treatment with bendamustin unless contraindications are existing or debulking is not indicated. Afterwards 6 cycles of induction therapy with GA101 and ibrutinib will be applied, each with a duration of 28 days. Primary endpoint overall Response rate will be assessed at final restaging. Patients benefitting from BIG treatment will enter the maintenance phase of the trial. Maintenance treatment will be continued if no unacceptable toxicity occurs until three months after negativity of minimal residual disease \[MRD\] is achieved in peripheral blood in patients with (clinical) complete response (CR) or (clinical) incomplete complete response \[CRi\] (confirmed by 2 consecutive testings of MRD within 3 months), progression of CLL, start of a subsequent therapy or up to 8 cycles of maintenance (each cycle with a duration of 84 calendar days = 3 months), whichever occurs first.

Petra Langerbeins, Adam Giza, Sandra Robrecht, Paula Cramer, Julia von Tresckow et al. (24 authors)

Blood2024-04-1525 citations

10.1182/blood.2023022564

Durable remissions following combined targeted therapy in patients with CLL harboring <i>TP53</i> deletions and/or mutations

Paula Cramer, Eugen Tausch, Julia von Tresckow, Adam Giza, Sandra Robrecht et al. (17 authors)

Blood2021-06-0412 citations

10.1182/blood.2020010484

Bendamustine, followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia (CLL2-BIO): primary endpoint analysis of a multicenter, open-label phase-II trial.

Cramer P, Tresckow JV, Robrecht S, Bahlo J, Fürstenau M, Langerbeins P, Pflug N, Al-Sawaf O, Heinz WJ, Vehling-Kaiser U, Dürig J, Tausch E, Hensel M, Sasse S, Fink AM, Fischer K, Kreuzer KA, Böttcher S, Ritgen M, Kneba M, Wendtner CM, Stilgenbauer S, Eichhorst B, Hallek M.

2021-02-0114 citations

10.3324/haematol.2019.223693

Comparison of different phase II studies using sequential combinations of targeted agents for treating chronic lymphocytic leukemia.

Von Tresckow Julia, Paula Cramer, Jasmin Bahlo, Sandra Robrecht, Othman Al‐Sawaf et al. (17 authors)

Journal of Clinical Oncology2018-05-20

10.1200/jco.2018.36.15_suppl.7513

CLL2-BXX Phase II trials: sequential, targeted treatment for eradication of minimal residual disease in chronic lymphocytic leukemia.

Cramer P, von Tresckow J, Bahlo J, Engelke A, Langerbeins P, Fink AM, Fischer K, Wendtner CM, Kreuzer KA, Stilgenbauer S, Böttcher S, Eichhorst B, Hallek M.

2018-02-2123 citations

10.2217/fon-2017-0442

Interventions

DRUGBendamustine

Debulking: 2 cycles of Bendamustine (70 mg/m² iv) will be administered before induction unless a contraindication is existing or it is not clinically indicated.

DRUGGA101

Induction GA101 iv infusion: Cycle 1: Day 1 100 mg Day 1 (or 2) 900 mg Day 8 1000 mg Day 15 1000 mg Cycle 2-6: Day 1 1000 mg Maintenance After the induction ibrutinib po 420 mg daily and GA101 iv 1000 mg every three months will be continued. GA101: Cycle 1-8 Day 1 1000 mg

DRUGIbrutinib

Ibrutinib will be administered as a daily oral dosage of 420 mg starting on cycle 2 day 1. Cycle 2-6: Day 1 420 mg daily Maintenance After the induction ibrutinib po 420 mg daily and GA101 iv 1000 mg every three months will be continued. Ibrutinib: Cycle 1-8 420 mg daily

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

1. documented CLL requiring treatment (irrespective if first- or relapse treatment) according to the criteria of the international Workshop of CLL \[iwCLL\] In case of previously treated patients, these 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-BIG trial: * chemotherapy within ≥ 28 days * antibody treatment within ≥ 14 days * kinase inhibitors, B-cell-lymphoma 2 \[BCL2\] -antagonists or immunomodulatory agents within ≥ 3 days * corticosteroids may be applied until the start of the BIG-regimen, these have to be reduced to an equivalent of ≤ 20mg prednisolon during treatment 2. Creatinine clearance ≥ 30 ml/min 3. Adequate hematologic function 4. Adequate liver function 5. Negative serological testing for hepatitis B, hepatitis-C RNA and negative HIV test within 6 weeks prior to registration 6. Age at least 18 years 7. Eastern Cooperative Oncology Group \[ECOG\] status 0 - 2; ECOG 3 is only permitted if related to CLL 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. Transformation of CLL 2. Known central nervous system (CNS) involvement 3. Patients with a history of confirmed progressive multifocal leukoencephalopathy \[PML\] 4. Malignancies other than CLL currently requiring systemic therapies 5. Uncontrolled infection requiring systemic treatment 6. Use of investigational agents which would interfere with the study drug within 28 days prior to registration 7. 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 comprise 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) 8. Known hypersensitivity to GA101, ibrutinib or any of the excipients 9. Requirement of treatment with strong cytochrome P450 3A4 \[CYP3A4\] -inhibitors/-inducers or anticoagulant with warfarin or phenprocoumon (marcumar) 10. History of stroke or intracranial hemorrhage within 6 months prior to registration 11. Pregnant women and nursing mothers 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 a minimum of 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

Design outcomes

Primary

Measure	Time frame	Description
Overall response rate (ORR)	84 days after first dose of last induction cycle	proportion of patients responding according to international working Group on chronic lymphocytic leukemia criteria

Secondary

Measure	Time frame	Description
Safety: Adverse events (AEs) and adverse events of special interest (AESI)	up to 48 months after first dose of study drug	Type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment.
minimal residual disease (MRD)	final restaging and during maintenance	Rate of MRD responses in peripheral blood measured by immunophenotyping

Countries

Germany

Outcome results

None listed