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

Chronic Lymphocytic Leukemia Clinical Trial

— ZFCR/ZBR  

Official title:

A Phase 2 Clinical Trial to Evaluate the Efficacy of Zanubrutinib Followed Zanubrutinib Plus FCR (Fludarabine Cyclophosphamide and Rituximab) / BR(Bendamustine and Rituximab) in Newly Diagnosed Symptomatic CLL/SLL (STOP Trial)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05287984
• Other study ID #: BDH-CLL-002-2022/02/14
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: March 22, 2022
• Est. completion date: November 29, 2024

Study information

• Verified date: March 2022
• Source: Institute of Hematology & Blood Diseases Hospital
• Contact: Shuhu Yi
• Phone: 86-22-23909106
• Email: yishuhua[@]ihcams.ac.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

The investigators designed timed FCR/BR treatment for BTK inhibitor Zanubrutinib monotherapy after continuous remission, which shortened the treatment time, deepened the depth of remission, and enabled some patients to achieve deep remission (MRD negative), and realized long-term survival after drug withdrawal. Treatment regimens: Zanubrutinib monotherapy for 12 months followed by 4 courses of immunochemotherapy with FCR or BR. Cohort 1 was designed to apply FCR for patients aged 65 years or younger who could tolerate FCR. Cohort 2 was designed to apply BR in patients older than 65 years or unable to tolerate FCR.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 63
• Est. completion date: November 29, 2024
• Est. primary completion date: June 28, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 1. 18 Years and older (Adult, Older Adult)
• 2. 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.
• 3. Confirmed diagnosis of CLL or SLL that meets the 2008 IWCLL criteria
• 4. 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
• 5. 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: ?=10% weight loss with no apparent cause in the previous 6 months; ? Severe fatigue (such as ECOG physical state =2 points; Unable to carry out regular activities); ? No evidence of infection, body temperature >38?, =2 weeks; (4) No evidence of infection, night sweats >1 month
• 6. ECOG performance status of 0, 1, or 2
• 7. The main organ functions met the following criteria within 7 days before treatment:

Blood routine examination criteria: platelet =30×10^9/L; Biochemical tests should meet the following criteria: Total bilirubin (TBIL) =1.5 times the upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase AST=2.5*ULN; Creatinine clearance rate = 30mL /min; Cardiac Doppler ultrasonography: Left ventricular ejection fraction (LVEF)= the lower limit of normal (50%).

• 8. Both men and women of reproductive age agreed to use reliable contraception throughout the study period and for up to four weeks after the end of treatment
• 9. Life expectancy = 6 months
• 10. Patients voluntarily participated in the study and signed informed consent

Exclusion Criteria:

• 1. Have been diagnosed or treated for malignancies other than CLL (including active CNS lymphoma) within the past year
• 2. Clinical evidence suggests that Richter's transformation occurs
• 3. 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
• 4. 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
• 5. 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.)
• 6. Clinical manifestations of central nervous dysfunction or CNS invasion
• 7. 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
• 8.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
• 9. Requires ongoing treatment with any medication which is a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor or strong CYP3A inducer
• 10. Females who are currently pregnant or breastfeeding, or at a childbearing age who are not using contraception
• 11. 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
• 12. Persistent uncontrolled bleeding
• 13. A history of life-threatening haemorrhage, especially from irreversible causes
• 14. High doses of several anticoagulants are required and cannot be stopped for a short time
• 15. evere allergy to the active ingredient or any excipients of the product

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Newly Diagnosed
• Small Lymphocytic Lymphoma

Intervention

Drug:
• Zanubrutinib, Fludarabine, cyclophosphamide and rituximab
Patients aged 65 years or younger who can tolerate FCR.
• Zanubrutinib, bendamustine, rituximab
For patients older than 65 years or who cannot tolerate FCR regimens.

Locations

Country	Name	City	State
China	Institute of Hematology & Blood Diseases Hospital	Tianjin	Tianjin

Sponsors (1)

Lead Sponsor	Collaborator
Institute of Hematology & Blood Diseases Hospital

Country where clinical trial is conducted

China, 

References & Publications (2)

Böttcher S, Ritgen M, Fischer K, Stilgenbauer S, Busch RM, Fingerle-Rowson G, Fink AM, Bühler A, Zenz T, Wenger MK, Mendila M, Wendtner CM, Eichhorst BF, Döhner H, Hallek MJ, Kneba M. Minimal residual disease quantification is an independent predictor of — View Citation

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; B — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	biological factors	To explore the effects of different biological factors on treatment response, MRD negative and survival.	up to 5 years
Primary	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	overall response rate(ORR)	Defined as the proportion of patients whose BICR was assessed for CR, CRi, or PR according to IWCLL 2018 criteria at or before initiation of subsequent antitumor therapy.	up to the end of 16 cycles of treatment (each cycle is 28 days)
Secondary	Complete response (CR)	Defined as the percentage of subjects who achieved CR after treatment in the conformance population and the intentionality treatment population.	up to the end of 16 cycles of treatment (each cycle is 28 days)
Secondary	Duration of tumor remission(DOR)	Defined as the time interval between the first documented remission of disease and the first documented evidence of PD for patients in the intentional-treatment population (ITT). Exit with no progress or no recorded time of disease progression, with the date of the last examination as the end date.	up to 5 years
Secondary	time to next treatment(TTNT)	Patients in the treatment-intentionality population (ITT) were defined from the beginning of first-line treatment to the beginning of back-line treatment or the time of death.	up to 5 years
Secondary	Progress-free survival(PFS)	the time from treatment initiation until disease progression or death, If there was no progress at the time of withdrawal or the time of disease progression was not recorded, the end date was the date of the last examination.	up to 5 years
Secondary	The time at which the median MRD turned positive	It was defined as the time for the median peripheral and/or bone marrow MRD to become positive in patients with CR/CRi and MRD negative in bone marrow and peripheral blood after the 16th cycle of treatment.	up to 5 years
Secondary	overall survival	Defined as the time interval from enrollment to death for patients in the treatment-intentionality population (ITT). If the patient remains alive or if it is not known whether the patient is alive or dead, the date of death will be adopted at the most recent point in time when the patient is known to be alive.	up to 5 years
Secondary	Safety of treatment regimens	Defined as treatment-related toxicity	up to 5 years