A Phase 3 interventional study of Fludarabine and Cyclophosphamide in Chronic Lymphocytic Leukemia, sponsored by German CLL Study Group. Completed at 161 sites in 10 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-12-30.
Sponsored by German CLL Study Group · Phase 3, Interventional, and Treatment
The aim of this study is to evaluate if standard chemoimmunotherapy (FCR, BR) in frontline treatment of physically fit CLL patients without del17p or TP 53 mutation can be replaced by combinations of targeted drugs (Venetoclax, Ibrutinib) with anti-CD20-antibodies (Rituximab, Obinutuzumab), which may induce extremely long lasting remissions.
Chemoimmunotherapy is the standard of care in first-line treatment of CLL patients without del17p or TP 53 mutation; physically fit patients are treated with fludarabine, cyclophosphamide and rituximab (FCR)1. Due to the high risk of severe neutropenias and infections with FCR, bendamustine and rituximab (BR) must be considered in patients aged >65 years.
However, these conventional chemoimmunotherapies are associated with side effects caused by the rather unspecific mode of action of the chemotherapy. Therefore, there is an urgent need for alternatives, especially chemotherapy-free regimens.
In first line treatment of elderly patients with CLL and coexisting conditions, the anti-CD20-antibody obinutuzumab is the new standard therapy. In the CLL11 trial the combination of obinutuzumab with chlorambucil proved to be safe and lead to markedly improved response rates as well as PFS times in comparison to chlorambucil alone or combined with rituximab.
The BCL2 antagonist venetoclax (GDC-0199/ABT-199) showed striking activity with tumor lysis syndrome as dose limiting toxicity in patients with relapsed and refractory CLL. 400 mg venetoclax was determined to be a safe and efficacious dose. Several patients treated with the combination of venetoclax and rituximab in relapsed refractory CLL even achieved MRD negativity. The FDA approved Venetoclax for the treatment of relapsed CLL with 17p/TP53 on 12th April 2016.
Therefore, venetoclax plus CD20-antibody based combinations have the potential to induce higher rates of MRD negativity in frontline therapy of CLL and concomitantly induce lower rates of toxicities so that chemotherapy might be replaced. Furthermore, venetoclax and obinutuzumab demonstrated synergistic activity in a preclinical study of a murine Non-Hodgkin lymphoma xenograft model, and additive activity in a CLL lymph node model. The combination appears tolerable in the firstline treatment of CLL patients with coexisting conditions whilst the toxicity profile of both drugs compares favorably to those of the chemotherapies currently used in the treatment of CLL. Consequently, it should be tested if rituximab can be replaced by obinutuzumab in combination with venetoclax in this trial.
Ibrutinib, a selective, irreversible small molecular inhibitor of Bruton´s Tyrosine Kinase (BTK), showed excellent responses and a safe toxicity profile9,10, even in combination with BR. Ibrutinib is approved for treatment of relapsed CLL as well as frontline therapy of CLL by the FDA and EMA (April 29th 2016).
The combination of ibrutinib and venetoclax showed synergy in primary CLL cells.
Consequently, the aim of the current trial is to evaluate if chemoimmunotherapy in the frontline treatment of physically fit patients in CLL can be replaced by combinations of these targeted drugs with anti-CD20-antibodies.
1,648 studies on the registry are indexed under Leukemia, Lymphocytic, Chronic, B-Cell; 245 are open to participants now.
This study's enrollment of 926 is above the median of 40 across 1,356 interventional studies indexed under Leukemia, Lymphocytic, Chronic, B-Cell.
Browse Leukemia, Lymphocytic, Chronic, B-Cell studies →German CLL Study Group is the lead sponsor of 37 studies on the registry; 4 are open to participants now.
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Exclusion Criteria:
Fertile men or women of childbearing potential unless:
Patients up to age 65: 6 cycles (q28d) of Fludarabine + Cyclophosphamide + Rituximab (FCR) Patients older than 65 years: 6 cycles (q28d) of Bendamustine + Rituximab (BR)
Drug: Fludarabine · Drug: Cyclophosphamide · Biological: Rituximab · Drug: Bendamustine
6 cycles (q28d) of RVe + 6 cycles (q28d) of Venetoclax (alone)
Biological: Rituximab · Drug: Venetoclax
6 cycles (q28d) of GVe + 6 cycles (q28d) of Venetoclax (alone)
Drug: Venetoclax · Biological: Obinutuzumab
6 cycles (q28d) of GIVe + 6 cycles (q28d) of Ibrutinib plus Venetoclax. Administration of ibrutinib will be continued for a maximum of 36 months or until MRD negativity, start of new anti-CLL therapy or inacceptable toxicity, whatever occurs first.
Drug: Venetoclax · Biological: Obinutuzumab · Drug: Ibrutinib
Fludarabine i.v.: cycles 1-6: 25 mg/m², d1-3, q28d
Also known as: Fludura
Cyclophosphamide i.v.: cycles 1-6: 250 mg/m², d1-3, q28d
Also known as: Endoxan
Rituximab i.v. (before chemotherapy): cycle 1: 375 mg/m², d0; cycles 2-6: 500 mg/m², d1; q28d
Also known as: MabThera, Rituxan
Bendamustine i.v.: cycles 1-6: 90mg/m², d1-2, q28d
Also known as: Ribomustin, Levact
Venetoclax p.o. (ramp-up: dose escalation until final dose is reached) cycle 1: 20 mg (2 tabl. at 10 mg), d22-28, q28d 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, q28d cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28, q28d
Also known as: Venclexta, Venclyxto
Obinutuzumab i.v. cycle 1: 100 mg, d1; 900 mg, d1(2); 1000 mg, d8+15, q28d cycles 2-6: 1000 mg, d1, q28d
Also known as: Gazyva, Gazyvaro
Ibrutinib p.o. cycles 1-12: 420 mg, d1-28, q28d cycles 13-36: 420 mg, d1-28, q28d
Also known as: Imbruvica
Miminimal residual disease (MRD) negativity rate in peripheral blood (PB)
Proportion of MRD negative patients at month15 based on the intention-to-treat population (ITT population), that is the number of MRD negative patients divided by the number of the ITT population. MRD negativity is defined as \<1 CLL-cell among 10,000 leukocytes analyzed \[0.01%\], i.e. \< 10-4. Primary outcome measure for the comparison of GVe vs. SCIT
Time frame: Month 15
Progression free survival (PFS)
Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines \[2008\]), or death from any cause, whichever occurs first. Primary outcome measure for the comparison GIVe vs. SCIT
Time frame: anticipated for January 2023 (after 213 events occured and 73 months after the first patient has been randomized
MRD negativity rate in PB
Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines \[2008\]), or death from any cause, whichever occurs first. Secondary outcome measure for all other comparisons with the exception of GVe vs. SCIT
Time frame: Month 15
MRD levels in PB
Time frame: Month 2, 9, 13 and later time points according to the discretion of the treating physician at local laboratories
MRD levels in bone marrow (BM)
Time frame: at final restaging (RE): 2 month after the end of the last treatment cycle
PFS
Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines \[2008\]), or death from any cause, whichever occurs first. Secondary outcome measure for all other comparisons with the exception of GIVe vs.SCIT
Time frame: anticipated for January 2023 (after 213 events occured and 73 months after the first patient has been randomized)
Overall response rate (ORR)
Time frame: Month 3, 9, 13 and 15
Rate of complete responses (CR) / complete responses with incomplete bone marrow recovery(CRi)
Complete response (CR) rate is defined by the proportion of patients having achieved a CR/CRi defined by the IWCLL guidelines as best response until and including the response assessment at Month 6, 9, 12 and 15 (= number of patients with best response CR/CRi divided by the ITT population).
Time frame: Interim staging (IST: cycle 4 d1), cycle 9 d1 (or final restaging (RE) for patients in the SCIT arm), IR (or three month after RE for patients in the SCIT arm respectively) and Month 15, with regard to best response achieved
Showing the first 100 of 161 sites across 10 countries.
Plan to share: No
Ran from Dec 2016 to primary completion in Feb 2024, 86 months.
Of 79 phase 3 interventional studies under Leukemia, Lymphocytic, Chronic, B-Cell, half reached primary completion within 59 months of starting (the median), counting those still running; a quarter within 43 and three quarters within 76. This study's 86 months is above that.
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This study is completed, as verified in Mar 2024. You cannot join it, but the record below documents what was studied.
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Studies of the drugs tested here: Rituximab · Venetoclax · Obinutuzumab · Ibrutinib
Leukemia, Lymphocytic, Chronic, B-Cell →
German CLL Study Group