| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Waldenström's Macroglobulinemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Waldenström's Macroglobulinemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10047801 |
| E.1.2 | Term | Waldenstrom's macroglobulinaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To test the efficacy of Bortezomib, Rituximab, Ibrutinib (B-RI) in patients with treatment naïve Waldenström's Macroglobulinemia (WM) assessing the 1-year progression free survival |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the anti-lymphoma activity of Bortezomib, Rituximab, Ibrutinib (B-RI) in patients with treatment naïve WM assessing response rates, time to treatment failure, remission duration, cause specific survival and overall survival and to assess the safety of this combination |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. In addition, pathological specimens have to be sent to the national pathological reference center at study inclusion. The positivity for CD20 positive can be assumed from any previous bone marrow immunohistochemistry or flow cytometry analysis performed up to 6 months prior to enrollment. Inclusion in the protocol 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 expressions. 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.
• Patients must have at least one of the following critera to initiate treatment as defined by “Consensus Panel Two” recommendations from the Second International Workshop on Waldenström Macroglobulinemia.
- Recurrent fever, night sweats, weight loss, fatigue (at least one of them)
- Hyperviscosity
- Lymphadenopathy which is either symptomatic or bulky (≥ 5cm 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
• World Health Organization (WHO)/ECOG performance status 0 to 2.
• Other criteria
- Age ≥ 18 years
- Life expectancy > 3 months.
- Baseline platelet count ≥ 100 x 10^9/L (if not due to BM involvement by the lymphoma), independent of any transfusions
- Absolute neutrophil count ≥ 1 x 10^9/L independent of growth factor support. 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 limitof 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/1.73m^2
• 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).
• 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.
• 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)
|
|
| E.4 | Principal exclusion criteria |
• 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)
• Patient with hypersensitivity to Bortezomib
• Patient with hypersensitivity to Rituximab
• 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 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 4 weeks prior to study inclusion.
• No consent for registration, storage and processing of the individual disease-characteristics
• St. John’s Wort with Ibrutinib
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon).
• Requires treatment with strong CYP3A 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the rate of 1-year progression free survival (1YPFS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1-year Progression Free Survival Rate (1YPFS) will be assessed by CT and immunofixation 1 year after first Administration of study medication |
|
| E.5.2 | Secondary end point(s) |
- Response rate (CR, VGPR, PR, MR) and overall response (ORR) four weeks after the end of induction therapy
- Best response
- Time to best response
- Time to first response
- Progression free survival
- Time to treatment failure
- Remission Duration
- Cause specific survival
- Overall survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Response rates (CR, VGPR, PR, MR) and overall response will be assessed by CT and immunofixation 4 weeks after end of induction treatment. Best response, progression free survival, time to best Response will be assessed in the time interval from the start of induction therapy to end of follow-up. Time to first response, time to treatment failure, remission duration, cause specific survival, overall survival, safety will be assessed from start of treatment until end of follow-up. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
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