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JOURNAL ONKOLOGIE – STUDIE
CLL17

Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients With Previously Untreated Chronic Lymphocytic Leukaemia (CLL)

Rekrutierend

NCT-Nummer:
NCT04608318

Studienbeginn:
März 2021

Letztes Update:
22.03.2021

Wirkstoff:
Ibrutinib, Venetoclax, Obinutuzumab

Indikation (Clinical Trials):
Leukemia, Leukemia, Lymphoid, Leukemia, Lymphocytic, Chronic, B-Cell

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
German CLL Study Group

Collaborator:
Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON), Nordic CLL Study Group (NCLLSG), Swiss Group for Clinical Cancer Research (SAKK), Cancer Trials Ireland, Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA), Grupo Español de Leucemia Linfoc

Studienleiter

Othman Al-Sawaf, Dr. med.
Principal Investigator
German CLL Study Group

Kontakt

Studienlocations
(1 von 1)

Gemeinschaftspraxis für Hämatologie & Onkologie
44263 Dortmund
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps

Studien-Informationen

Brief Summary:

The aim of this study is to compare the efficacy of continuous ibrutinib monotherapy with

fixed-duration venetoclax plus obinutuzumab and fixed-duration ibrutinib plus venetoclax by

measuring progression-free survival (PFS) in patients with previously untreated CLL.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Documented CLL requiring treatment according to iwCLL criteria.

2. Age at least 18 years.

3. Life expectancy ≥ 6 months.

4. Ability and willingness to provide written informed consent and to adhere to the study

visit schedule and other protocol requirements.

5. Adequate bone marrow function independent of growth factor or transfusion support

within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL:

1. Absolute neutrophil count ≥ 1.0 × 109/L

2. Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia clearly due to CLL

(per the discretion of the investigator), platelet count should be ≥ 10 × 109/L

3. Total haemoglobin ≥ 9 g/dL (without transfusion support, unless anaemia is due to

CLL)

6. GFR >30ml/min directly measured with 24hr urine collection, calculated according to

the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x

bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method.

a. For patients with creatinine values within the normal range the calculation of the

clearance is not necessary. Dehydrated patients with an estimated creatinine clearance

less than 30 ml/min may be eligible if a repeat estimate after adequate hydration is >

30 ml/min.

7. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the

institutional ULN value, unless directly attributable to the patient's CLL or to

Gilbert's Syndrome.

8. Negative serological testing for hepatitis B (HbsAg negative 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 month until 12 months after last treatment cycle),

negative testing for hepatitis C RNA within 6 weeks prior to registration for study

screening (i.e. PCR only required when serology was positive).

9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.

Exclusion criteria:

1. Any prior CLL-specific therapies (except corticosteroid treatment administered due to

necessary immediate intervention; within the last 10 days before start of study

treatment, only dose equivalents up to 20 mg prednisolone are permitted).

2. Transformation of CLL (Richter transformation). When Richter transformation is

suspected, PET-CT and/or biopsy should be performed to rule out transformation.

3. Patients with a history of PML.

4. An individual organ/ system impairment score of 4 as assessed by the CIRS definition

limiting the ability to receive the study treatment 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).

5. Malignancies other than CLL currently requiring systemic therapies, not being treated

with curative intent before (unless the malignant disease is in a stable remission due

to the discretion of the treating physician or showing signs of progression after

curative treatment.

6. Uncontrolled or active infection.

7. Patients with known infection with human immunodeficiency virus (HIV).

8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/ inducers (incl. up to

7 days prior to study treatment start).

9. Anticoagulant therapy with warfarin or phenprocoumon, (alternative anticoagulation is

allowed (e.g. DOACs), but patients must be properly informed about the potential risk

of bleeding under treatment with ibrutinib).

10. History of stroke or intracranial hemorrhage within 6 months prior to registration for

study screening.

11. Known bleeding disorders

12. Child B / C liver cirrhosis

13. Use of investigational agents which might interfere with the study drug within 28 days

prior to registration for study screening.

14. Vaccination with live vaccines 28 days prior to registration for study screening.

15. Major surgery less than 30 days before start of study treatment.

16. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal

antibodies, known sensitivity or allergy to murine products.

17. Known hypersensitivity to any active substance or to any of the excipients of one of

the drugs used in the trial.

18. Pregnant women and nursing mothers (a negative pregnancy test is required for all

women of childbearing potential within 7 days before start of study treatment; further

pregnancy testing will be performed monthly).

19. Fertile men or women of childbearing potential unless:

1. surgically sterile or ≥ 2 years after the onset of menopause

2. willing to use two methods of reliable contraception including one highly

effective contraceptive method (Pearl Index <1) and one additional effective

(barrier) method during study treatment and for 18 months after the end of study

treatment.

20. Legal incapacity.

21. Prisoners or subjects who are institutionalized by regulatory or court order.

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

Studien-Rationale

Primary outcome:

1. Investigator-assessed progression-free survival (PFS) (Time Frame - Up to 80 month):
Time from randomization to the first occurrence of progression or relapse (determined using standard iwCLL guidelines), or death from any cause, whichever occurs first



Secondary outcome:

1. Rates of undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM) (Time Frame - At final restaging (RE): 18 months after start of treatment and additional BM assessment approx. 12 months after RE):
Undetectable MRD (uMRD) is defined as <10-4 (=1 CLL-cell per 10,000 leukocytes analyzed).The uMRD rate is defined as the proportion of patients having achieved uMRD.

2. MRD levels in PB at different time points (Time Frame - Up to 80 month):
MRD is defined as the number of CLL-cells that can be detected in peripheral blood (PB) or bone marrow (BM). MRD values will be categorized into negative (<10-4) and positive (≥10-4)

3. Overall response rate (ORR) (Time Frame - At final restaging (RE): 18 months after start of treatment):
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.

4. CR/CRi rate (Time Frame - At final restaging (RE): 18 months after start of treatment):
Proportion of patients having achieved a CR or CRi as best response (= number of patients with best response CR or CRi divided by the number of the intention-to-treat population (ITT) population)

5. Incidence of safety parameters such as adverse events (AE) and adverse events of particular/special interest (AEPI/AESI) (Time Frame - Up to 80 month):
Type, frequency, severity and relationship to study treatment.of AEs and AEPIs/AESIs

Studien-Arme

  • Experimental: I (Ibrutinib)
    Ibrutinib p.o. will be administered until occurrence of unacceptable toxicity, progression of CLL or end of trial, whichever occurs first.
  • Experimental: VG (Obinutuzumab + Venetoclax)
    12 cycles (q 28d): Obinutuzumab i.v. + Venetoclax p.o. will be administered for 6 cycles, followed by 6 additional cycles of Venetoclax alone
  • Experimental: VI (Venetoclax + Ibrutinib)
    15 cycles (q 28d): Ibrutinib p.o. + Venetoclax p.o. will be administered for a total of 12 cycles with a prior Ibrutinib monotherapy lead-in of 3 cycles

Geprüfte Regime

  • Ibrutinib (Imbruvica):
    Cycles 1 - X: 420 mg daily, d1-28 p.o.
  • Venetoclax (ABT-199, Venclyxto):
    Arm VG Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o. Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o. Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o. Arm VI Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o. Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o.
  • Obinutuzumab (GA101, Gazyvaro):
    Cycle 1: (100 mg, d1 + 900 mg, d2) or 1000 mg, d1; 1000 mg, d8 + d15 i.v. Cycle 2 - 6: 1000 mg, d1 i.v.

Quelle: ClinicalTrials.gov


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