RITUXIMAB for Waldenstrom's macroglobulinaemia

Inclusion criteria

• {"criterion_text":"-Clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM, diagnosed by a reference pathology center. In addition, pathological specimens have to be sent to the national pathological reference center at study inclusion. The positivity for CD20 can be assumed from any previous bone marrow immunohistochemistry or flow cytometry analysis performed up to 4 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.\n-Men must agree not to father a child for the duration of therapy and 12 months after (use of a condom) and must agree to advice a female partner to use a highly effective method of birth control.\n-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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.\n-Patients must have at least one of the following criteria to initiate treatment as defined by “Consensus Panel Two” recommendations from the Second International Workshop on Waldenström’s Macroglobulinemia: 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; IgM related immune hemolytic anemia and/or thrombocytopenia; Nephropathy related to WM; Amyloidosis related to WM; Hemoglobin ≤10g/dL; Platelet count <100x10^9/L; Serum monoclonal protein >5g/dL, even with no overt clinical symptoms; Low or absent IgG serum levels\n-World Health Organization (WHO)/ECOG performance status 0 to 2.\n-Age ≥ than 18 years\n-Life expectancy >3 months\n-Baseline platelet count ≥ 100 x 10^9/L (if not due to BM involvement by the lymphoma), independent of any transfusions\n-Absolute neutrophil count ≥ 1 x 10^9/L independent of growth factor support\n-Meet the following pretreatment laboratory criteria at the Screening visit conducted within 28 days of study enrollment: ASAT (SGOT): ≤ 3 times the upper limit of institutional laboratory normal value; ALAT (SGPT): ≤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 (Cockcroft-Gault) ≥ 40 mL/min/1.73m^2\n-Women of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming postmenopausal must agree to use a highly effective method of birth control for the duration of the therapy up to 3 months after end of therapy with Bortezomib and Ibrutinib and up to 12 months after the end of therapy with Rituximab. 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 combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner or sexual abstinence. However, due to Ibrutinib administered in this study, those women using hormonal methods of birth control must add a barrier method. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Contraception and pregnancy testing are required according the CTFG recommendations (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf)"}

Exclusion criteria

• {"criterion_text":"-Prior systemic treatment of the WM (plasmapheresis and short – term administration of corticosteroids < 6 weeks administered at a dose equivalent to < 20 mg/day prednisone is allowed)\n-Prior allergic reaction or severe anaphylactic reaction related to humanized or murine monoclonal antibody\n-Central Nervous System involvement by lymphoma\n-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).\n-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 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\n-Subjects with ≥ Grade 2 neuropathy.\n-Recent major surgery (within 4 weeks prior to study inclusion)\n-History of stroke or intracranial haemorrhage within 6 months prior to study inclusion\n-Women who are pregnant as well as women who are breast-feeding and do not consent to discontinue breast-feeding.\n-Participation in another clinical trial within four weeks prior to study inclusion\n-No consent for registration, storage and processing of the individual disease-characteristics\n-Patient with hypersensitivity to Bortezomib\n-St. John’s Wort with Ibrutinib\n-Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon)\n-Requires treatment with strong CYP3A inhibitors\n-Vaccinated with live, attenuated vaccines within 4 weeks prior to study inclusion\n-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\n-Patient with hypersensitivity to Rituximab\n-Patient with hypersensitivity to Ibrutinib\n-Serious medical or psychiatric illness likely to interfere with participation in this clinical study.\n-Uncontrolled viral infection\n-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.\n-Congenital or acquired severe immunodeficiency not attributed to lymphoma (clinical appearance: recurrent infections, necessity of immunoglobulin substitution therapy, patients after transplantation)\n-Known interstitial lung disease"}

Primary endpoints

• {"endpoint_text":"-The primary endpoint is the rate of 1-year progression free survival (1YPFS).","definition_or_measurement_approach":"Rate of 1-year progression-free survival (1YPFS). Progression-free survival (PFS) is calculated from the date of start of treatment to the date of progression (as defined in Appendix A) or date of death; the primary endpoint is the proportion alive and progression-free at 1 year."}

Secondary endpoints

• {"endpoint_text":"-The response rates (CR, VGPR, PR, MR) and overall response rate (CR, VGPR, PR, MR) are evaluated 4 weeks after the end of induction treatment.","definition_or_measurement_approach":"Response rates (CR, VGPR, PR, MR) assessed 4 weeks after end of induction treatment."}
• {"endpoint_text":"-Best response (at least achieving a MR) is determined in the time interval from the start of induction therapy to end of follow-up.","definition_or_measurement_approach":"Best response is the highest response achieved from start of induction to end of follow-up."}
• {"endpoint_text":"-Time to best response is defined as the time from the start of induction to best response the patient achieves (CR, VGPR, PR, MR).","definition_or_measurement_approach":"Measured as time from start of induction therapy to date of best response (CR, VGPR, PR, MR)."}
• {"endpoint_text":"-Time to first response is defined as the time from the start of induction to first response (MR, PR, VGPR or CR).","definition_or_measurement_approach":"Measured as time from start of induction therapy to first documented response (MR, PR, VGPR or CR)."}
• {"endpoint_text":"-Time to treatment failure (TTF) is defined as the 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 alive without progression and relapse will be censored at the latest tumor assessment date.","definition_or_measurement_approach":"TTF measured from start of induction to treatment discontinuation for any reason; censoring at last tumor assessment if no event."}
• {"endpoint_text":"-Remission duration will be calculated in patients with response (CR, VGPR, PR, MR) from the date of response to the date of progression, relapse or death from any cause. Patients alive without progression and relapse will be censored at the latest tumor assessment date.","definition_or_measurement_approach":"Duration measured from date of response to date of progression, relapse or death; censoring at last tumor assessment if none."}
• {"endpoint_text":"-PFS will be calculated from the date of start of treatment to the following events: the date of progression (as defined in Appendix A) and the date of death if it occurred earlier. Patients alive without progression and relapse will be censored at the latest tumor assessment date.","definition_or_measurement_approach":"PFS measured from treatment start to progression or death; censoring at last tumor assessment."}
• {"endpoint_text":"-Cause specific survival is defined as the period from the start of induction treatment to death from lymphoma or lymphoma related cause; death unrelated to WM is considered as a competing event.","definition_or_measurement_approach":"Measured from start of induction to death from lymphoma or lymphoma-related cause; competing events considered for unrelated death."}
• {"endpoint_text":"-Overall survival is defined as the period from the start of induction treatment to death from any cause. Patients who have not died until the time of the analysis will be censored at their last contact date.","definition_or_measurement_approach":"Measured from start of induction to death from any cause; censoring at last contact date for survivors."}
• {"endpoint_text":"-Safety including treatment associated adverse events.","definition_or_measurement_approach":"Safety endpoints include collection and assessment of treatment-emergent/adverse events according to standard safety reporting; specific grading/definitions not detailed in the dataset provided."}

Germany

Earliest CTIS Part Ii Submission Date

10-10-2024

Latest Decision Or Authorization Date

15-05-2026

Processing Time Days

582

Number Of Sites

11

Number Of Participants

41

Greece

Earliest CTIS Part Ii Submission Date

05-12-2024

Latest Decision Or Authorization Date

15-05-2026

Processing Time Days

526

Number Of Sites

1

Number Of Participants

12

Primary sponsor

Full Name

University Hospital Of Ulm AöR

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"Universitaetsklinikum Ulm AöR","duties_or_roles":"8","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Belgium","full_name":"Clinigen Clinical Supplies Management","duties_or_roles":"14","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"Coronis Research S.A.","duties_or_roles":"1,12","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Ludwig-Maximilians-Universitaet Muenchen","duties_or_roles":"10","organisation_type":"Educational Institution"}