Zanubrutinib, Ixazomib and Dexamethasone in Patients With Treatment Naive Waldenstrom's Macroglobulinemia

A Phase 2 Clinical Trial to Evaluate the Efficacy of Zanubrutinib Plus Ixazomib and Dexamethasone in Newly Diagnosed Symptomatic Waldenström Macroglobulinemia

This study aims to evaluate the efficacy of BTK inhibitor Zanubrutinib combined with Ixazomib and Dexamethasone (ZID) for the newly diagnosed Waldenstrom Macroglobulinemia. This ZID regimen will be given up to 24 months and stopped for observation. We propose this combination will improve the deep remission (≥VGPR) compared to single Zanubrutinib or IRD regimen and can be a time-limited regimen which will reduce the life-time therapy and benefit the patients.

Study Overview

• Status: Completed
• Conditions: Waldenström Macroglobulinemia
• Intervention / Treatment: Drug: Zanubrutinib,Ixazomib and Dexamethasone

Detailed Description

As Waldenstrom Macroglobulinemia cells always have two or three components tumor cells, including lymphocyte, Lymphoplasmacytic cells and plasma cells. We designed a oral regimen to target both lymphoma cells (Zanubrutinib) and plasma cells (Ixazomib plus Dexamethasone) to eliminate the tumor cells of WM. We propose this combination will improve the deep remission of WM (≥VGPR) . Zanubrutinib will be given 160mg Bid per day, up to 24 months, Ixazomib 4mg per week and Dexamethasone 20mg per week for three weeks, every 4 weeks one course. ID will be given 6 course as introduction and then one course every 12 weeks for up to 24 months. At the last ID course, Zanubrutinib will be stopped. The last ID course is to prevent the bounce of IgM because of Zanubrutinib discontinue.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300020
      • Institute of Hematology & Blood Diseases Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The gender of the patient is not limited, and the age is ≥18 years old;
2. Must meet WM's diagnostic standards;

3. The patient is an untreated or patient who has not undergone standard treatment. The specific conditions are as follows:

   1. No combined chemotherapy with 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

4. 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.
5. ECOG score ≤ 2 points
6. 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.
7. The patient's expected survival time is ≥ 3 months.

Exclusion Criteria:

1. Malignant tumors (including active central nervous system lymphoma) other than B-NHL have been diagnosed or treated within the past year;
2. There is clinical evidence that large cell lymphoma transformation has occurred;
3. 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;
4. 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;
5. 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.
6. Central nervous system dysfunction with clinical manifestations or central invasion (Bing-Neel syndrome);
7. Patients who have undergone major surgery (not including lymph node biopsy) within the past 14 days or expected major surgery during treatment;
8. 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.
9. Need to receive strong cytochrome P450 (CYP) 3A inhibitor treatment.
10. Women who are pregnant or breastfeeding, women of childbearing age who have not taken contraception;
11. Allergy to the drugs used.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ZID regimen; Zanubrutinib, 160mg orally, twice a day; Ixazomib, 4 mg orally, day 1, 8, 15; Dexamethasone, 20mg orally, days 1, 8, 15.

Drug: Zanubrutinib,Ixazomib and Dexamethasone; Zanubrutinib, 160mg orally, twice a day; Ixazomib, 4 mg orally, day 1, 8, 15; Dexamethasone, 20mg orally, days 1, 8, 15；Ixazomib and dexamethasone every 4 weeks of a cycle, with induction of 6 cycles, and then maintain every 12 weeks, up to 6 cycles (96 cycles in total). Zanubrutinib is taken orally twice a day for up to 96 cycles, with a reduction in the last ID cycle. ZID regimen will continue 6 cycles after reaching the maximum response after introduction section.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Deep remission response rate	≥VGPR after 6 cycles introduction	up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response (CR)	Disappearance of monoclonal protein on immunofixation (both serum and urine); No histologic evidence of bone marrow involvement; Resolution of adenopathy and/or organomegaly on CT; Resolution of clinical signs or symptoms attributed to WM/LPL.	up to 12 months
Progress-free survival (PFS)	the time from treatment initiation until disease progression or death	up to 5 years
Duration of response (DoR)	the time from best response (R) to progression/death (P/D)	up to 5 years
Overall survival (OS)	The percentage of patients in treatment group who are still alive for a certain period of time after they were diagnosed with Waldenstrom's Macroglobulinemia.	up to 36 months
Time to next treatment (TTNT)	time from end of primary treatment to institution of next therapy	up to 5 years
Overall response	minimor response+partial response+VGPR+CR	up to 5 year

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Investigators: Principal Investigator: Shuhua Yi, Chinese Academy of Medical Sciences and Peking Union Medical College

Publications and helpful links

General Publications

• Treon SP, Xu L, Guerrera ML, Jimenez C, Hunter ZR, Liu X, Demos M, Gustine J, Chan G, Munshi M, Tsakmaklis N, Chen JG, Kofides A, Sklavenitis-Pistofidis R, Bustoros M, Keezer A, Meid K, Patterson CJ, Sacco A, Roccaro A, Branagan AR, Yang G, Ghobrial IM, Castillo JJ. Genomic Landscape of Waldenstrom Macroglobulinemia and Its Impact on Treatment Strategies. J Clin Oncol. 2020 Apr 10;38(11):1198-1208. doi: 10.1200/JCO.19.02314. Epub 2020 Feb 21.
• Treon SP, Xu L, Hunter Z. MYD88 Mutations and Response to Ibrutinib in Waldenstrom's Macroglobulinemia. N Engl J Med. 2015 Aug 6;373(6):584-6. doi: 10.1056/NEJMc1506192. No abstract available.
• Castillo JJ, Meid K, Gustine JN, Dubeau T, Severns P, Hunter ZR, Yang G, Xu L, Treon SP. Prospective Clinical Trial of Ixazomib, Dexamethasone, and Rituximab as Primary Therapy in Waldenstrom Macroglobulinemia. Clin Cancer Res. 2018 Jul 15;24(14):3247-3252. doi: 10.1158/1078-0432.CCR-18-0152. Epub 2018 Apr 16.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Actual): December 6, 2022
• Study Completion (Actual): December 6, 2022

Study Registration Dates

• First Submitted: July 4, 2020
• First Submitted That Met QC Criteria: July 4, 2020
• First Posted (Actual): July 9, 2020

Study Record Updates

• Last Update Posted (Actual): February 11, 2026
• Last Update Submitted That Met QC Criteria: February 9, 2026
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Dexamethasone; Zanubrutinib; Ixazomib; Waldenström Macroglobulinemia
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hemic and Lymphatic Diseases; Waldenstrom Macroglobulinemia; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Pregnadienetriols; Dexamethasone; zanubrutinib; ixazomib
• Other Study ID Numbers: IIT2020002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No