Efficacy of first line Bortezomib, Rituximab, Ibrutinib (B-RI) for patients with treatment naive Waldenström’s Macroglobulinemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Hospital Of Ulm AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

11 Sep 2019 → ongoing

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Janssen Pharmaceutica NV (part of the Pharmaceutical Companies of Jonson & Johnson) · F. Hoffmann-La Roche Ltd

External identifiers

EU CT number

2022-500584-12-00

EudraCT number

2017-004362-95

ClinicalTrials.gov

NCT03620903

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective of the trial is to test the efficacy of Bortezomib, Rituximab, Ibrutinib (B-RI) in patients with treatment naïve Waldenström´s Macroglobulinemia (WM) assessing the rate of the 1-year progression free survival.

Secondary objectives 1

1. Secondary objectives of the trial are 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.

Conditions and MedDRA coding

Waldenström’s Macroglobulinemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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.
2. 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
3. World Health Organization (WHO)/ECOG performance status 0 to 2.
4. Age ≥ than 18 years
5. Life expectancy >3 months
6. Baseline platelet count ≥ 100 x 10^9/L (if not due to BM involvement by the lymphoma), independent of any transfusions
7. Absolute neutrophil count ≥ 1 x 10^9/L independent of growth factor support
8. 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
9. 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)
10. 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.
11. 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.

Exclusion criteria 24

1. 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)
2. Patient with hypersensitivity to Bortezomib
3. Patient with hypersensitivity to Rituximab
4. Patient with hypersensitivity to Ibrutinib
5. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
6. Uncontrolled viral infection
7. 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.
8. Congenital or acquired severe immunodeficiency not attributed to lymphoma (clinical appearance: recurrent infections, necessity of immunoglobulin substitution therapy, patients after transplantation)
9. Known interstitial lung disease
10. Prior allergic reaction or severe anaphylactic reaction related to humanized or murine monoclonal antibody
11. Central Nervous System involvement by lymphoma
12. 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).
13. 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
14. Subjects with ≥ Grade 2 neuropathy.
15. Recent major surgery (within 4 weeks prior to study inclusion)
16. History of stroke or intracranial haemorrhage within 6 months prior to study inclusion
17. Women who are pregnant as well as women who are breast-feeding and do not consent to discontinue breast-feeding.
18. Participation in another clinical trial within four weeks prior to study inclusion
19. No consent for registration, storage and processing of the individual disease-characteristics
20. St. John’s Wort with Ibrutinib
21. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon)
22. Requires treatment with strong CYP3A inhibitors
23. Vaccinated with live, attenuated vaccines within 4 weeks prior to study inclusion
24. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 10

1. 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.
2. Best response (at least achieving a MR) is determined in the time interval from the start of induction therapy to end of follow-up.
3. Time to best response is defined as the time from the start of induction to best response the patient achieves (CR, VGPR, PR, MR).
4. Time to first response is defined as the time from the start of induction to first response (MR, PR, VGPR or CR).
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Safety including treatment associated adverse events.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Hospital Of Ulm AöR

Sponsor organisation

University Hospital Of Ulm AöR

Address

Albert-Einstein-Allee 29, Eselsberg Eselsberg

City

Ulm

Postcode

89081

Country

Germany

Scientific contact point

Organisation

University Hospital Of Ulm AöR

Contact name

Prof. Dr. med Christian Buske

Public contact point

Organisation

University Hospital Of Ulm AöR

Contact name

Prof. Dr. med Christian Buske

Third parties 4

Locations

2 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications