Brief Title
Efficacy of First Line B-RI for Treatment Naive Waldenström's Macroglobulinemia
Official Title
Efficacy of First Line Bortezomib, Rituximab, Ibrutinib (B-RI) for Patients With Treatment Naive Waldenström's Macroglobulinemia
Brief Summary
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.
Detailed Description
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
1 year progression free survival
Secondary Outcome
Response rate
Condition
Waldenstrom Macroglobulinemia
Intervention
Ibrutinib / Bortezomib / Rituximab
Study Arms / Comparison Groups
Bortezomib-Rituximab-Ibrutinib
Description: 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);
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
53
Start Date
September 11, 2019
Completion Date
September 2029
Primary Completion Date
December 2022
Eligibility Criteria
Inclusion Criteria
- Clinicopathological diagnosis of WM as defined by consensus panel one of the Second
International Workshop on WM, diagnosed by a reference pathology center. Pathological
diagnosis has to occur before study inclusion. In addition, pathological specimens
have to be sent to the national pathological reference center at study inclusion. The
positivity for Cluster of Differentiation (CD) 20 can be assumed from any previous
bone marrow immunohistochemistry or flow cytometry analysis performed up to 6 months
prior to enrollment. Inclusion in the study will be based on morphological and
immunological criteria. Immunophenotyping will be performed in each center and saved
locally. Flow cytometry of bone marrow and blood cells will include at least one
double staining and assess the expression of the following antigens: surface
immunoglobulin, CD19, CD20, CD5, CD10 and CD23. Patients are eligible if tumor cells
express the following antigens: CD19, CD20, and if they are negative for CD5, CD10 and
CD23 expression. Patients with tumor cells positive for CD5 and/or CD23 and
morphologically similar to WM cells may be included after ruling out other low-grade
B-cell malignancies.
- Presence of at least one criterion for initiation of therapy, according to the 2nd
Workshop on WM:
- Recurrent fever, night sweats, weight loss, fatigue (at least one of them)
- Hyperviscosity
- Lymphadenopathy which is either symptomatic or bulky (≥5 cm in maximum diameter)
- Symptomatic hepatomegaly and/or splenomegaly
- Symptomatic organomegaly and/or organ or tissue infiltration
- Peripheral neuropathy due to WM
- Symptomatic cryoglobulinemia
- Cold agglutinin anemia
- Immunoglobulin M (IgM) related immune hemolytic anemia and/or thrombocytopenia
- Nephropathy related to WM
- Amyloidosis related to WM
- Hemoglobin ≤10g/dL
- Platelet count <100x109/L
- Serum monoclonal protein >5g/dL, even with no overt clinical symptoms
- Low or absent IgG serum levels
- World Health Organization (WHO)/Eastern Co-operative Oncology Group (ECOG) performance
status 0 to 2.
- Other criteria:
- Age ≥ than 18 years
- Life expectancy >3 months.
- Baseline platelet count >100x10exponential (E)9/L if not due to bone marrow (BM)
involvement by the lymphoma, independent of any transfusions
- absolute neutrophil count >1x10E9/L independent of growth factor support.
- Meet the following pretreatment laboratory criteria at the Screening visit
conducted within 28 days of study enrollment:
- aspartate aminotransferase (AST): <3 times the upper limit of institutional
laboratory normal value
- alanine aminotransferase (ALAT): <3 times the upper limit of institutional
laboratory normal value
- Total Bilirubin: < 1.5 times the upper limit of institutional laboratory
normal value, unless clearly related to the disease (except if due to
Gilbert's syndrome)
- Serum creatinine: ≤ 2 times the upper limit of institutional laboratory
normal value or estimated Glomerular Filtration Rate (cockroft-gault ≥ 40
mL/min/1.73m2)
- Premenopausal fertile females must agree to use a highly effective method of birth
control for the duration of the therapy up to 6 months after end of therapy. A highly
effective method of birth control is defined as those which result in a low failure
rate (i.e. less than 1% per year) when used consistently and correctly such as
implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs),
sexual abstinence or vasectomised partner.
- Men must agree not to father a child for the duration of therapy and 12 months after
and must agree to advice a female partner to use a highly effective method of birth
control.
- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.
- Affiliation to a social security scheme (relevant for France only)
Exclusion Criteria:
- Prior systemic treatment of the WM (plasmapheresis and short - term administration of
corticosteroids < 4 weeks administered at a dose equivalent to < 20 mg/day prednisone
is allowed)
- Patient with hypersensitivity to Bortezomib
- Patient with hypersensitivity to MabThera
- Patient with hypersensitivity to Ibrutinib
- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.
- Uncontrolled viral infection
- Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or
active Hepatitis B Virus infection or any uncontrolled active systemic infection
requiring intravenous (IV) antibiotics.
- Congenital or acquired severe immunodeficiency not attributed to lymphoma (clinical
appearance: recurrent infections, necessity of immunoglobulin substitution therapy,
patients after transplantation)
- Known interstitial lung disease
- Prior allergic reaction or severe anaphylactic reaction related to humanized or murine
monoclonal antibody.
- Central Nervous System involvement by lymphoma
- Prior history of malignancies unless the subject has been free of the disease for ≥ 5
years. Exceptions include the following:
- Basal cell carcinoma of the skin,
- Squamous cell carcinoma of the skin,
- Carcinoma in situ of the cervix,
- Carcinoma in situ of the breast,
- Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b).
- Uncontrolled illness including, but not limited to:
- Uncontrolled diabetes mellitus (as indicated by metabolic derangements and/or severe
diabetes mellitus related uncontrolled organ complications)
- Chronic symptomatic congestive heart failure (Class New York Heart Association (NYHA)
III or IV).
- Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6
months
- Clinically significant cardiac arrhythmia that is symptomatic or requires treatment,
or asymptomatic sustained ventricular tachycardia.
- Known pericardial disease
- acute diffuse infiltrative pulmonary and pericardial disease
- Subjects with ≥ Grade 2 neuropathy.
- Recent major surgery (within 4 weeks prior to study inclusion)
- History of stroke or intracranial haemorrhage within 6 months prior to study inclusion
- Women who are pregnant as well as women who are breast-feeding and do not consent to
discontinue breast-feeding.
- Participation in another clinical trial within four weeks prior to study inclusion
- No consent for registration, storage and processing of the individual
disease-characteristics and course as well as information of the family physician
about study participation
- St. John's Wort with Ibrutinib
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
phenprocoumon).
- Requires treatment with strong cytochrome P (CYP) 3A inhibitors.
- Vaccinated with live, attenuated vaccines within 4 weeks prior to study inclusion.
- Person of legal age who is incapable of comprehending the nature, significance and
implications of the clinical trial and of determining his/her will in the light of
these facts
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Christian Buske, MD, ,
Location Countries
Germany
Location Countries
Germany
Administrative Informations
NCT ID
NCT03620903
Organization ID
ECWM-2
Secondary IDs
2017-004362-95
Responsible Party
Sponsor-Investigator
Study Sponsor
Christian Buske
Collaborators
University of Ulm
Study Sponsor
Christian Buske, MD, Principal Investigator, University of Ulm
Verification Date
March 2022