Clinical trial NCT05914662: Zanubrutinib Plus BR in Newly Diagnosed Symptomatic WM
Official title: Phase II Clinical Study of Zanubrutinib Combined With Bendamustine and Rituximab (ZBR) for Time-limited Treatment of Waldenstrom Macroglobulinemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Waldenstrom Macroglobulinemia
Keywords: Waldenstrom macroglobulinemia
Zanubrutinib
newly diagnosed
Lead sponsor: Institute of Hematology & Blood Diseases Hospital, China
Sponsor class: OTHER
First posted: 2023-06-22
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients were treated with ZBR regimen for 6 cycles, followed by Zanubrutinib monotherapy for 6 months.
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Best combined complete response (CR) and very good partial response (VGPR)
timeFrame: up to the end of 12 cycles of treatment(each cycle is 28 days)
Secondary outcomes:
measure: Overall objective response rate (ORR), complete response rate(CR),major response rate(MR)
timeFrame: up to the end of 12 cycles of treatment(each cycle is 28 days)
measure: Time to response, time to best response
timeFrame: up to the end of 12 cycles of treatment(each cycle is 28 days)
measure: Overall survival(OS)
timeFrame: Up to 3 years after the end of treatment
measure: Progression free survival(PFS)
timeFrame: Up to 3 years after the end of treatment
measure: Duration of Response
timeFrame: Up to 3 years after the end of treatment
measure: Time to Next Treatment
timeFrame: Up to 3 years after the end of treatment
measure: Safety of treatment regimens
timeFrame: Up to 3 years after the end of treatment
Other outcomes:
Locations:
city: Tianjin
country: China
facility: Institute of Hematology & Blood Diseases Hospital
state: Tianjin
Study officials:
affiliation: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
name: Shuhua Yi, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 2020 EHA EP1194
citation: 2021 ASCO 8049