Zanubrutinib Plus BR in Newly Diagnosed Symptomatic WM

NCT ID: NCT05914662

Last Updated: 2024-08-28

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

42 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-02-15

Study Completion Date

2025-12-15

Brief Summary

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This study aims to evaluate the long-term efficacy of BTK inhibitor Zanubrutinib combined bendamustine and rituximab (ZBR) for time-limited treatment of Waldenstrom macroglobulinemia, The combination therapy is expected to improve the remission depth, prolong the remission time, and improve the progression-free survival and overall survival of newly diagnosed WM patients. On the one hand, the patients have to bear a long-term economic burden, which is often difficult for some patients to adhere to for a long time. On the other hand, in the course of long-term treatment of BTKi, drug resistance and intolerable side effects are prone to occur. At the same time, it can prevent the disease rebound after the withdrawal of BTKi, so as to achieve the phased withdrawal of WM

Detailed Description

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WM not only has the characteristics of lymphoma, such as lymphadenopathy, hepatosplenomegaly, and tumor cells expressing CD20, but also has the characteristics of myeloma, such as secreting monoclonal IgM, and tumor cells expressing plasma cell differentiation marker CD38, etc. Clinical studies have also shown that BR regimen and BTK inhibitor zanubrutinib are effective for WM.

This study aims to evaluate the long-term efficacy of BTK inhibitor Zanubrutinib combined bendamustine and rituximab (ZBR) for time-limited treatment of Waldenstrom macroglobulinemia, The combination therapy is expected to improve the remission depth, prolong the remission time, and improve the progression-free survival and overall survival of newly diagnosed WM patients. On the one hand, the patients have to bear a long-term economic burden, which is often difficult for some patients to adhere to for a long time. On the other hand, in the course of long-term treatment of BTKi, drug resistance and intolerable side effects are prone to occur. At the same time, it can prevent the disease rebound after the withdrawal of BTKi, so as to achieve the phased withdrawal of WM. This prospective phase II study was designed to evaluate the rate of deep response in newly diagnosed symptomatic WM. Eligible patients received ZBR for 6 cycles followed by zanubrutinib monotherapy for an additional 6 months.

Conditions

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Waldenstrom Macroglobulinemia

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Patients were treated with ZBR regimen for 6 cycles, followed by Zanubrutinib monotherapy for 6 months.
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Zanubrutinib, bendamustine, rituximab combination therapy Group

Patients were treated with ZBR regimen for 6 cycles, followed by zanubrutinib monotherapy for an additional 6 months.

Group Type EXPERIMENTAL

Zanubrutinib, Bendamustine and Rituximab

Intervention Type DRUG

Zanubrutinib, 160mg orally, twice a day; Bendamustine 70 mg/m2 on days 1 and 2 of each cycle; Rituximab (375 mg/m2 intravenously on day 0 of each cycle. ZBR was administered every 4 weeks for a total of 6 cycles, followed by maintenance therapy with zanubrutinib monotherapy for another 6 months.

Interventions

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Zanubrutinib, Bendamustine and Rituximab

Zanubrutinib, 160mg orally, twice a day; Bendamustine 70 mg/m2 on days 1 and 2 of each cycle; Rituximab (375 mg/m2 intravenously on day 0 of each cycle. ZBR was administered every 4 weeks for a total of 6 cycles, followed by maintenance therapy with zanubrutinib monotherapy for another 6 months.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* The gender of the patient is not limited, and the age is ≥18 years old;
* Must meet WM's diagnostic standards;
* The patient is an untreated or patient who has not undergone standard treatment.
* The specific conditions are as follows:

1. No combined chemotherapy with BTKi, BR, RCD, VRD, CHOP and COP
2. No treatment regimen containing fludarabine
3. Chlorambucil or cyclophosphamide for less than 4 weeks (alone or in combination with adrenal glucocorticoids)
4. The above treatment did not reach the treatment response (MR)
5. If the above treatment has been applied, the treatment needs to be stopped for 2 weeks before entering the group to start treatment
* The indications for the treatment of indolent lymphoma mainly include (at least one of the following conditions):

1. Symptomatic hyperviscosity;
2. Symptomatic peripheral neuropathy;
3. Amyloidosis;
4. Cold agglutinin disease; cryoglobulinemia;
5. Disease-related cytopenia (Hb\<100 g/L, PLT\<100×10\^9/L);
6. Giant lymph nodes;
7. Those with systemic systemic symptoms: for two weeks/recurrent fever (above 38℃) and not caused by infection, or Night sweats and/or weight loss \>10% within 6 months;
8. The disease progresses rapidly, for example, the lymph nodes increase by more than 50% within 2 months, and/or peripheral blood lymphocytes absolute value doubling time \<6 months, and/or rapid hemoglobin or platelet non-autoimmune causes slow down
9. When there is evidence that the disease has transformed.
* ECOG score ≤ 2 points
* Laboratory examination: neutrophils ≥ 0.75×10\^9/L; platelets ≥ 50×10\^9/L; total bilirubin ≤ 2.5 times upper limit; alanine aminotransferase/aspartate aminotransferase ≤3 times upper limit. Creatinine clearance rate ≥ 30ml/min.
* The patient's expected survival time is ≥ 3 months.

Exclusion Criteria

* Malignant tumors (including active central nervous system lymphoma) other than B-NHL have been diagnosed or treated within the past year;
* There is clinical evidence that large cell lymphoma transformation has occurred;
* Non-lymphoma-related liver and kidney damage: alanine aminotransferase (ALT)\> 3 times the upper limit of normal value, aspartate aminotransferase (AST)\> 3 times the upper limit of normal value, total bilirubin (TBIL)\> upper limit of normal value 2 Times, serum creatinine clearance rate \<30ml/min;
* Other serious medical conditions will affect the study (such as uncontrolled diabetes, gastric ulcers, other serious cardiopulmonary diseases, etc.). The decision-making power belongs to the researcher;
* Known history of infection with human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics.
* Central nervous system dysfunction with clinical manifestations or central invasion (Bing-Neel syndrome);
* Patients who have undergone major surgery (not including lymph node biopsy) within the past 14 days or expected major surgery during treatment;
* Inability to swallow capsules or suffer from malabsorption syndrome, diseases that significantly affect gastrointestinal function, have undergone gastric or small bowel resection, symptomatic inflammatory bowel disease or ulcerative colitis, partial or complete intestinal obstruction.
* Need to receive strong cytochrome P450 (CYP) 3A inhibitor treatment.
* Women who are pregnant or breastfeeding, women of childbearing age who have not taken contraception;
* Allergy to the drugs used.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Institute of Hematology & Blood Diseases Hospital, China

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Shuhua Yi, Dr.

Role: PRINCIPAL_INVESTIGATOR

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

Locations

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Institute of Hematology & Blood Diseases Hospital

Tianjin, Tianjin Municipality, China

Site Status RECRUITING

Countries

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China

Central Contacts

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Shuhua Yi, Dr.

Role: CONTACT

86-22-23909106

Lugui Qiu, Dr.

Role: CONTACT

86-22-23909172

Facility Contacts

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Shuhua Yi, Dr.

Role: primary

86-22-23909106

Lugui Qiu, Dr.

Role: backup

86-22-23909172

References

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Dimopoulos MA, Garcia-Sanz R, Gavriatopoulou M, Morel P, Kyrtsonis MC, Michalis E, Kartasis Z, Leleu X, Palladini G, Tedeschi A, Gika D, Merlini G, Kastritis E, Sonneveld P. Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood. 2013 Nov 7;122(19):3276-82. doi: 10.1182/blood-2013-05-503862. Epub 2013 Sep 4.

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Dimopoulos MA, Tedeschi A, Trotman J, Garcia-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenstrom's Macroglobulinemia. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenstrom's Macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. doi: 10.1056/NEJMoa1802917. Epub 2018 Jun 1.

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Treon SP, Soumerai JD, Branagan AR, Hunter ZR, Patterson CJ, Ioakimidis L, Chu L, Musto P, Baron AD, Nunnink JC, Kash JJ, Terjanian TO, Hyman PM, Nawfel EL, Sharon DJ, Munshi NC, Anderson KC. Lenalidomide and rituximab in Waldenstrom's macroglobulinemia. Clin Cancer Res. 2009 Jan 1;15(1):355-60. doi: 10.1158/1078-0432.CCR-08-0862.

Reference Type BACKGROUND
PMID: 19118065 (View on PubMed)

Paludo J, Abeykoon JP, Shreders A, Ansell SM, Kumar S, Ailawadhi S, King RL, Koehler AB, Reeder CB, Buadi FK, Dispenzieri A, Lacy MQ, Dingli D, Witzig TE, Go RS, Gonsalves WI, Kourelis T, Warsame R, Leung N, Habermann TM, Hayman S, Lin Y, Kyle RA, Rajkumar SV, Gertz MA, Kapoor P. Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenstrom macroglobulinemia. Ann Hematol. 2018 Aug;97(8):1417-1425. doi: 10.1007/s00277-018-3311-z. Epub 2018 Apr 3.

Reference Type BACKGROUND
PMID: 29610969 (View on PubMed)

Castillo JJ, Abeykoon JP, Gustine JN, Zanwar S, Mein K, Flynn CA, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, King R, Yang G, Hunter ZR, Advani RH, Palomba ML, Ansell SM, Gertz MA, Kapoor P, Treon SP. Partial response or better at six months is prognostic of superior progression-free survival in Waldenstrom macroglobulinaemia patients treated with ibrutinib. Br J Haematol. 2021 Feb;192(3):542-550. doi: 10.1111/bjh.17225. Epub 2020 Nov 18.

Reference Type BACKGROUND
PMID: 33207010 (View on PubMed)

2020 EHA EP1194

Reference Type BACKGROUND

2021 ASCO 8049

Reference Type BACKGROUND

Other Identifiers

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IIT2022070

Identifier Type: -

Identifier Source: org_study_id

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