Zanubrutinib Plus BR in Newly Diagnosed Symptomatic WM

NCT05914662 | Recruiting Phase 2 DMC

• 1 other identifier: IIT2022070
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Waldenstrom Macroglobulinemia

Keywords

Waldenstrom macroglobulinemia; Zanubrutinib; newly diagnosed

Outcome Measures

Primary Outcomes (1)

• Best combined complete response (CR) and very good partial response (VGPR)

  To evaluate the efficacy of zanubrutinib plus bendamustine and rituximab (ZBR) regimen in the treatment of newly diagnosed WM patients, mainly the best deep response rate, namely the best deep response rate (VGPR and above).

  up to the end of 12 cycles of treatment(each cycle is 28 days)

Secondary Outcomes (7)

• Overall objective response rate (ORR), complete response rate(CR),major response rate(MR)

  up to the end of 12 cycles of treatment(each cycle is 28 days)

• Time to response, time to best response

  up to the end of 12 cycles of treatment(each cycle is 28 days)

• Overall survival(OS)

  Up to 3 years after the end of treatment

• Progression free survival(PFS)

  Up to 3 years after the end of treatment

• Duration of Response

  Up to 3 years after the end of treatment

Study Arms (1)

Zanubrutinib, bendamustine, rituximab combination therapy Group

EXPERIMENTAL

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

Drug: Zanubrutinib, Bendamustine and Rituximab

Interventions

Zanubrutinib, Bendamustine and Rituximab 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.

Zanubrutinib, bendamustine, rituximab combination therapy Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• No combined chemotherapy with BTKi, BR, RCD, VRD, CHOP and COP
• No treatment regimen containing fludarabine
• Chlorambucil or cyclophosphamide for less than 4 weeks (alone or in combination with adrenal glucocorticoids)
• The above treatment did not reach the treatment response (MR)
• 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):
• Symptomatic hyperviscosity;
• Symptomatic peripheral neuropathy;
• Amyloidosis;
• Cold agglutinin disease; cryoglobulinemia;
• Disease-related cytopenia (Hb\<100 g/L, PLT\<100×10\^9/L);

You may not qualify if:

• 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.

Sponsors & Collaborators

• Institute of Hematology & Blood Diseases Hospital, China: lead

Study Sites (1)

Institute of Hematology & Blood Diseases Hospital

Tianjin, Tianjin Municipality, 300020, China

RECRUITING

Related Publications (11)

• Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Durk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. doi: 10.1016/S0140-6736(12)61763-2. Epub 2013 Feb 20.

  PMID: 23433739 BACKGROUND

• 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.

  PMID: 24004667 BACKGROUND

• Castillo JJ, Meid K, Gustine JN, Leventoff C, White T, Flynn CA, Sarosiek S, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Branagan AR, O'Donnell E, Raje N, Yee AJ, Patterson CJ, Hunter ZR, Treon SP. Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia. Leukemia. 2022 Feb;36(2):532-539. doi: 10.1038/s41375-021-01417-9. Epub 2021 Sep 16.

  PMID: 34531537 BACKGROUND

• 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.

  PMID: 29856685 BACKGROUND

• Trotman J, Opat S, Gottlieb D, Simpson D, Marlton P, Cull G, Munoz J, Tedeschi A, Roberts AW, Seymour JF, Atwal SK, Yu Y, Novotny W, Holmgren E, Tan Z, Hilger JD, Huang J, Tam CS. Zanubrutinib for the treatment of patients with Waldenstrom macroglobulinemia: 3 years of follow-up. Blood. 2020 Oct 29;136(18):2027-2037. doi: 10.1182/blood.2020006449.

  PMID: 32698195 BACKGROUND

• Kastritis E, Gavriatopoulou M, Kyrtsonis MC, Roussou M, Hadjiharissi E, Symeonidis A, Repoussis P, Michalis E, Delimpasi S, Tsatalas K, Tsirigotis P, Vassou A, Vervessou E, Katodritou E, Gika D, Terpos E, Dimopoulos MA. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenstrom macroglobulinemia: final analysis of a phase 2 study. Blood. 2015 Sep 10;126(11):1392-4. doi: 10.1182/blood-2015-05-647420. No abstract available.

  PMID: 26359434 BACKGROUND

• 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.

  PMID: 19118065 BACKGROUND

• 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.

  PMID: 29610969 BACKGROUND

• 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.

  PMID: 33207010 BACKGROUND

• 2020 EHA EP1194

  BACKGROUND

• 2021 ASCO 8049

  BACKGROUND

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia

Interventions

zanubrutinib; Bendamustine Hydrochloride; Rituximab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Shuhua Yi, Dr.

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

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Shuhua Yi, Dr.

CONTACT

86-22-23909106; yishuhua@ihcams.ac.cn

Lugui Qiu, Dr.

CONTACT

86-22-23909172; qiulg@ihcams.ac.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients were treated with ZBR regimen for 6 cycles, followed by Zanubrutinib monotherapy for 6 months.

Study Record Dates

• First Submitted: June 13, 2023
• First Posted: June 22, 2023
• Study Start: February 15, 2023
• Primary Completion: March 15, 2025
• Study Completion: December 15, 2025
• Last Updated: August 28, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)