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Waldenstrom Macroglobulinemia

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Rituximab

Bortezomib

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Cycle 1:

Rituximab: 375 mg/m2 intravenously (i.v) day 1; Bortezomib:1.6 mg/ m2 subcutanously (SC) day 1,8,15; Ibrutinib: 420 mg orally (p.o.) day 1-28;

Cycle 2-6 Rituximab: 1400 mg absolute SC day 1; Bortezomib:1.6 mg/ m2 SC day 1,8,15; Ibrutinib: 420 mg p.o. day 1-28;

Maintenance I (1 cycle = 56 days):

Ibrutinib 420 mg p.o. daily, until evidence of progressive disease or no longer tolerated by the subject (for a maximum of 10 years); Rituximab 1400 mg absolute SC day 1, every second month for 24 months (month 7-30);

Maintenance II (1 cycle = 84 days):

Ibrutinib 420 mg p.o. daily, until evidence of progressive disease or no longer tolerated by the subject (for a maximum of 10 years);

Induction (Rituximab / Bortezomib / Ibrutinib), Maintenance I (Ibrutinib / Rituximab), Maintenance II (Ibrutinib)

Ibrutinib / Bortezomib / Rituximab

Christian Buske, MD

In Waldenström macroglobulinemia (WM) conventional chemotherapy induces only low complete remission (CR) rates and responses of short duration compared to other indolent lymphomas. Thus innovative approaches are needed which combine excellent activity and tolerability in patients with WM, who are mostly of advanced age. The immunochemotherapy DRC (dexamethasone, rituximab, cyclophosphamide) was shown to be highly effective in patients with WM without inducing major hematological toxicities. On the other hand the proteasome inhibitor bortezomib showed substantial activity as a single agent in WM with only very few side effects when given in a weekly schedule. Recent data confirmed high activity with low toxicity for ibrutinib in relapsed WM patients as single agent therapy. Based on these observations it is the aim of this study to investigate the efficacy and toxicity of the chemotherapy-free combination bortezomib, rituximab, ibrutinib (B-RI) in treatment naïve WM patient.

In Waldenström's macroglobulinemia (WM) conventional chemotherapy induces only low complete remission (CR) rates and responses of short duration compared to other indolent lymphomas. Thus innovative approaches are needed which combine excellent activity and tolerability in patients with WM, who are mostly of advanced age. Today, chemotherapy in combination with the anti-cluster of differentiation (CD) 20 antibody rituximab is still the backbone of treatment in patients with WM and is recommended as first line in national and international treatment guidelines. With the approval of Ibrutinib by the European Medicines Agency (EMA) 2015 for patients with relapsed WM or for patients not eligible for chemotherapy with treatment naïve WM treatment landscape has changed in this lymphoma subtype and there is an urgent need to evaluate to which extent chemotherapy-free approaches add clinical benefit to the patient. The treatment in the "European Consortium for Waldenström's Macroglobulinemia" (ECWM)-2 trial will test, whether the chemotherapy-free approach, which is given orally (ibrutinib) and subcutaneously (bortezomib and rituximab from cycle 2 onwards) (B-RI) will approach the efficacy of chemotherapy containing treatment concepts, but avoids chemotherapy associated toxicity. From the perspective of single agent ibrutinib, this regimen tests whether ibrutinib can be further optimized by adding rituximab and bortezomib. The combination of rituximab and ibrutinib was tested in comparison to rituximab/placebo in a large international phase III trial on behalf of the European Consortium for Waldenström's Macroglobulinemia in relapsed and first line WM, and results were recently published: in this trial no unexpected toxicity of the combination ibrutinib/rituximab was reported. Furthermore, ibrutinib/rituximab was significantly superior to rituximab/placebo with regard to response rates and PFS. From the perspective of the established rituximab/bortezomib regimen, the combination of B-RI will evaluate whether adding ibrutinib to this combination will add any benefit for the patient.

To this end, the aim of the study is to assess the toxicity and efficacy of B-RI in an exploratory phase II trial.

Efficacy of First Line B-RI for Treatment Naive Waldenström's Macroglobulinemia

Efficacy of First Line Bortezomib, Rituximab, Ibrutinib (B-RI) for Patients With Treatment Naive Waldenström's Macroglobulinemia

The primary endpoint is the rate of 1 year progression free survival (1YPFS).

response rates (CR, VGPR, PR, MR) and overall response rate (CR, VGPR, PR, MR)

time from the start of induction to best response the patient achieves (CR, VGPR, PR, MR).

time from the start of induction to first response (MR, PR, VGPR or CR).

time of start of induction treatment to discontinuation of therapy for any reason including death from any cause, progression, toxicity or add-on of new anti-cancer therapy.

patients with response (CR, VGPR, PR, MR) from the date of response to the date of progression, relapse or death from any cause.

date of start of treatment to the following events: the date of progression and the date of death if it occurred earlier.

period from the start of induction treatment to death from lymphoma or lymphoma related cause

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Efficacy of First Line B-RI for Treatment Naive Waldenström's Macroglobulinemia	NCT03620903	Waldenstrom Mac...	Ibrutinib / Bor...	18 Years -	University of Ulm
Efficacy of First Line B-RI for Treatment Naive Waldenström's Macroglobulinemia	NCT03620903	Waldenstrom Mac...	Ibrutinib / Bor...	18 Years -	University of Ulm

Spots Global Cancer Trial Database for waldenstrom macroglobulinemia, ibrutinib, bortezomib