Zanubrutinib Followed Zanubrutinib Plus FCR / BR in Newly Diagnosed Symptomatic CLL/SLL

NCT05287984 | Unknown Phase 2 DMC

• 1 other identifier: BDH-CLL-002-2022/02/14
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to evaluate the long-term efficacy of BTK inhibitor Zanubrutinib monotherapy , sequential Zanubrutinib combined (Fludarabine, cyclophosphamide and rituximab /bendamustine and rituximab)FCR/BR regimen by a limited period of treatment for the newly diagnosed Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). The investigators propose this combination will improve the MRD negative rate of patients with CR/CRi after treatment was significantly higher than that of FCR chemotherapy can be a time-limited regimen which will reduce the life-time therapy and benefit the patients.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Newly Diagnosed

Keywords

chronic lymphocytic leukemia; Small Lymphocytic Lymphoma; newly diagnosed; Zanubrutinib

Outcome Measures

Primary Outcomes (1)

• MRD negative rate of CR patients

  The negative MRD rate of patients with CR at the end of 16 cycles of treatment

  up to the end of 16 cycles of treatment (each cycle is 28 days)

Secondary Outcomes (8)

• overall response rate(ORR)

  up to the end of 16 cycles of treatment (each cycle is 28 days)

• Complete response (CR)

  up to the end of 16 cycles of treatment (each cycle is 28 days)

• Duration of tumor remission(DOR)

  up to 5 years

• time to next treatment(TTNT)

  up to 5 years

• Progress-free survival(PFS)

  up to 5 years

Other Outcomes (1)

• biological factors

  up to 5 years

Study Arms (2)

ZFCR regimen

EXPERIMENTAL

Patients aged 65 years or younger who can tolerate FCR： Patients in this group will receive zanubrutinib monotherapy for 12 months, then receive 4 cycles of zanubrutinib, fludarabine, cyclophosphamide and rituximab(ZFCR). Efficacy evaluation and MRD test of peripheral blood and bone marrow were performed at the 17th cycle after 16 cycles to obtain study end point data. Patients with CR/CRi and MRD negative could stop taking zanubrutinib, and other patients could stop taking zanubrutinib or continue treatment. Follow-up and efficacy assessment were conducted every three months.

Drug: Zanubrutinib, Fludarabine, cyclophosphamide and rituximab

ZBR regimen

EXPERIMENTAL

For patients older than 65 years or who cannot tolerate FCR regimens: Patients in this group will receive zanubrutinib monotherapy for 12 months, then receive 4 cycles of bendamostine and rituximab(BR). Efficacy evaluation and MRD test of peripheral blood and bone marrow were performed at the 17th cycle after 16 cycles to obtain study end point data. Patients with CR/CRi and MRD negative could stop taking zanubrutinib and other patients could stop taking zanubrutinib or continue treatment.

Drug: Zanubrutinib, bendamustine, rituximab

Interventions

Zanubrutinib, Fludarabine, cyclophosphamide and rituximab DRUG

Patients aged 65 years or younger who can tolerate FCR.

Also known as: ZFCR regimen

ZFCR regimen

Zanubrutinib, bendamustine, rituximab DRUG

For patients older than 65 years or who cannot tolerate FCR regimens.

Also known as: ZBR regimen

ZBR regimen

Eligibility Criteria

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

You may qualify if:

• \. 18 Years and older (Adult, Older Adult)
• \. Age \>65 years or age ≤65 years with creatinine clearance of 30-69 mL/min or patients with a cumulative Disease Rating Scale (CIRS-G) score greater than 6 point were enrolled in cohort 2 , other patients were enrolled in cohort 1.
• \. Confirmed diagnosis of CLL or SLL that meets the 2008 IWCLL criteria
• \. The patients are untreated or without prior systemic therapy for disease, the specific conditions are as follows:
• a) Prior treatment with a fludarabine or treatment with bendamustine or rituximab regimen
• b) Not treated with Chlorambucil, or treated with Chlorambucil for less than 4 weeks (alone or in combination with adrenal glucocorticoid)
• c) If the above treatment has been applied, it is necessary to stop treatment for 2 weeks before joining the group for treatment
• \. Treatment indications for CLL mainly include (meeting at least one of the following conditions):
• a) Evidence of progressive bone marrow failure presenting as progressive decrease in hemoglobin and/or platelets
• b) Splenomegaly (e.g., \>6cm below the left costal margin) or progressive or symptomatic splenomegaly
• c) giant lymph node enlargement (longest diameter \>10cm) or progressive or symptomatic lymph node enlargement
• d) Progressive lymphocytosis, such as lymphocytosis \>50% within 2 months, or lymphocyte multiplication time (LDT) \<6 months. When the initial lymphocyte was \<30×109/L, LDT alone could not be used as a treatment indication
• e) Autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) do not respond well to corticosteroids or other standard treatments
• f) Symptoms associated with at least one of the following diseases: ①≥10% weight loss with no apparent cause in the previous 6 months; ② Severe fatigue (such as ECOG physical state ≥2 points; Unable to carry out regular activities); ③ No evidence of infection, body temperature \>38℃, ≥2 weeks; (4) No evidence of infection, night sweats \>1 month
• \. ECOG performance status of 0, 1, or 2

You may not qualify if:

• \. Have been diagnosed or treated for malignancies other than CLL (including active CNS lymphoma) within the past year
• \. Clinical evidence suggests that Richter's transformation occurs
• \. Non-lymphoma-related liver and kidney function impairment: ALT \> 3 times the upper limit of normal value, AST \> 3 times the upper limit of normal value, TBIL \> 2 times the upper limit of normal value, serum creatinine clearance \<30ml/min
• \. Other serious medical conditions, such as uncontrolled diabetes, gastric ulcers, and other serious heart and lung diseases, may affect this study. The right to make judgments belongs to the researcher
• \. Diagnosed human immunodeficiency virus (HIV) infection or active hepatitis B virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics.
• (Note: Active HBV infection was defined as a.HBV DNA quantification ≥2000 IU/ mL; b. ALT≥2 times normal upper limit; c. To exclude hepatitis caused by other causes, such as the disease itself or drugs, the three conditions must be met simultaneously. Patients with active HBV infection at initial diagnosis and non-active HBV infection after anti-HBV treatment can be included in this study on the premise of adequate anti-HBV treatment.)
• \. Clinical manifestations of central nervous dysfunction or CNS invasion
• \. Patients who have had major surgery (excluding lymph node biopsy) within the past 14 days or who are expected to require major surgery as part of their treatment
• Unable to swallow capsules or malabsorption syndrome, disease that significantly affects gastrointestinal function, previous gastrectomy or small bowel resection, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
• \. Requires ongoing treatment with any medication which is a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor or strong CYP3A inducer
• \. Females who are currently pregnant or breastfeeding, or at a childbearing age who are not using contraception
• \. Clinically significant cardiovascular abnormalities (NYHA classification: III/IV) (Annex 3), patients with myocardial infarction, malignant arrhythmia (including QTC≥480ms), unsatisfactory blood pressure control with antihypertensive drugs (systolic blood pressure ≥150 mmHg, diastolic blood pressure ≥100 mmHg), and uncontrolled angina pectoris within 6 months before enrollment
• \. Persistent uncontrolled bleeding
• \. A history of life-threatening haemorrhage, especially from irreversible causes
• \. High doses of several anticoagulants are required and cannot be stopped for a short time

Sponsors & Collaborators

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

Study Sites (1)

Institute of Hematology & Blood Diseases Hospital

Tianjin, Tianjin Municipality, 300020, China

Location

Related Publications (2)

• Davids MS, Brander DM, Kim HT, Tyekucheva S, Bsat J, Savell A, Hellman JM, Bazemore J, Francoeur K, Alencar A, Shune L, Omaira M, Jacobson CA, Armand P, Ng S, Crombie J, LaCasce AS, Arnason J, Hochberg EP, Takvorian RW, Abramson JS, Fisher DC, Brown JR; Blood Cancer Research Partnership of the Leukemia & Lymphoma Society. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2019 Aug;6(8):e419-e428. doi: 10.1016/S2352-3026(19)30104-8. Epub 2019 Jun 14.

  PMID: 31208944 RESULT

• Bottcher S, Ritgen M, Fischer K, Stilgenbauer S, Busch RM, Fingerle-Rowson G, Fink AM, Buhler A, Zenz T, Wenger MK, Mendila M, Wendtner CM, Eichhorst BF, Dohner H, Hallek MJ, Kneba M. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012 Mar 20;30(9):980-8. doi: 10.1200/JCO.2011.36.9348. Epub 2012 Feb 13.

  PMID: 22331940 RESULT

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

zanubrutinib; fludarabine; Cyclophosphamide; Rituximab; Bendamustine Hydrochloride

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

Study Officials

• Shuhua Yi

  Blood disease hospital, Chinese Academic Medical School

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Shuhu Yi

CONTACT

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

Lugui Qiu

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: open label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 26, 2022
• First Posted: March 18, 2022
• Study Start: March 22, 2022
• Primary Completion: June 28, 2024
• Study Completion: November 29, 2024
• Last Updated: March 31, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)