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

  • STATUS
    Recruiting
  • End date
    Sep 7, 2029
  • participants needed
    53
  • sponsor
    Christian Buske
Updated on 7 October 2020
platelet count
cancer
remission
cyclophosphamide
lymphoma
rituximab
monoclonal antibodies
dexamethasone
neutrophil count
monoclonal antibody therapy
bortezomib
monoclonal protein
immunoglobulin
ibrutinib
lymphadenopathy
indolent lymphoma
cold agglutinin

Summary

In Waldenstrm 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 nave WM patient.

Description

In Waldenstrm'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 nave 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 Waldenstrm'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 Waldenstrm'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.

Details
Treatment Ibrutinib
Clinical Study IdentifierNCT03620903
SponsorChristian Buske
Last Modified on7 October 2020

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Eligibility

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Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Lymphoproliferative disorders or Waldenstrom's Macroglobulinemia or Lymphoproliferative Disorder or Waldenstrom Macroglobulinemia?
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
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