Trial Title:
Zanubrutinib With Obinutuzumab in Untreated Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
NCT ID:
NCT06544785
Condition:
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Conditions: Official terms:
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Obinutuzumab
Zanubrutinib
Conditions: Keywords:
zanubrutinib
obinutuzumab
untreated CLL/SLL
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Zanubrutinib Oral Product
Description:
Zanubrutinib drug product is supplied as 80 mg strengths in capsules for oral
administration.
In both arms A and B, zanubrutinib 320 mg will be taken qDay with or without food.
Patients will take zanubrutinib with water at approximately the same time every day.
Arm group label:
Arm Zanubrutinib+early Obinutuzumab
Arm group label:
Arm Zanubutinib+late Obinutuzumab
Other name:
Zanubrutinib
Intervention type:
Drug
Intervention name:
Obinutuzumab
Description:
Each dose of obinutuzumab is 1000 mg administered intravenously, per institutional
standards, with the exception of the first infusion in Cycle 2 (arm A) or Cycle 13 (arm
B). It is recommended that the initial 1000 mg dose be administered over Day 1 (100 mg)
and Day 2 (900 mg). For subjects who tolerate the initial 100 mg dose well and required
no dose interruption or modification of the infusion rate, the treating physician may opt
to administer the remaining 900 mg on Day 1.
Arm A: patients will receive obinutuzumab on days 1 (100 mg), 2 (or day 1 continued, 900
mg), 8 and 15 (1000 mg) of the cycle 2 of zanubrutinib treatment, and on the day 1 of
cycles 3-7 (1000 mg).
Arm B: patients will receive obinutuzumab on days 1 (100 mg), 2 ( (or day 1 continued,
900 mg), 8 and 15 (1000 mg) of the cycle 13 of zanubrutinib treatment, and on the day 1
of cycles 14-18 (1000 mg).
Arm group label:
Arm Zanubrutinib+early Obinutuzumab
Arm group label:
Arm Zanubutinib+late Obinutuzumab
Summary:
The goal of this phase II randomized open label study is to compare the rate of complete
remission (CR) with undetectable minimal residual disease (uMRD) obtained with
zanubrutinib in combination with obinutuzumab with two different schedules of
administration of obinutuzumab (starting obinutuzumab at cycle 2 or 12 months) in
patients with previously untreated Chronic Lymphocytic Leukemia (CLL) or Small
Lymphocytic Lymphoma (SLL). There is scarce information about which is the most
appropriate schedule of combining the BTKi and the anti-CD20 monoclonal antibody, and
whether treatment can be safely stopped in those patients attaining deep responses (CR
with uMRD) remains to be determined.
Response will be assessed after 20 cycles of treatment for the primary objective of the
study. Patients attaining uMRD will stop treatment with zanubrutinib, whereas the rest of
patients will continue on treatment with zanubrutinib until progression, unacceptable
toxicity, or trial completion, whichever comes first.
Detailed description:
This a multicenter, phase 2 randomized, open label study of the Spanish Group of CLL
(GELLC) for patients with untreated CLL/SLL with 2 arms of treatment. In this study, 106
patients from 20 centers in Spain with untreated CLL/SLL will be randomized (1:1) to arm
A (n= 53) or arm B (n= 53). The randomization will be stratified according to the
presence/absence of deletion/mutation 17p/TP53 at the time of inclusion and based on the
randomization list generated by the study statistician.
Arm A: Patients will be treated with the combination of zanubrutinib 320 mg P.O qDay and
obinutuzumab, starting obinutuzumab at cycle 2 to reduce infusion-related reactions.
Intravenous obinutuzumab will be given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and
15 (1000 mg) of cycle 2 and on day 1 (1000 mg) of cycles 3-7.
Arm B: Patients will start treatment with zanubrutinib 320 mg P.O qDay in monotherapy.
After 12 cycles of zanubrutinib patients will be treated with the combination of
zanubrutinib and obitnutuzumab. Intravenous obinutuzumab will be given on days 1 (100
mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 13 and on day 1 (1000 mg) of
cycles 14-18.
Response will be assessed after 20 cycles of treatment for the primary objective of the
study. Patients that in the evaluation of cycle 20 who achieve uMRD (<0.01% tumour cells
by flow cytometry) will stop treatment with zanubrutinib, whereas the rest of patients
will continue on treatment with zanubrutinib until progression, unacceptable toxicity or
trial completion, whichever comes first. Patients who achieve an uMRD in bone marrow
beyond C20, will also be allowed to stop the treatment, whereas the rest of patients will
continue on treatment with zanubrutinib until progression, unacceptable toxicity, or
trial completion, whichever comes first.
In addition, the efficacy and safety of the combination therapy with two different
administration schedules of obinutuzumab will be analysed through the following outcome
measures: i) Overall response rate, including Complete Remission (CR), CR with incomplete
marrow recovery (CRi), Partial Remission (PR), and partial response with lymphocytosis;
ii) MRD analysis; iiI) Duration of response and progression-free survival (PFS); iv)
Safety: type, frequency, and severity of adverse events (AEs) and relationship of AEs to
zanubrutinib or the combination of zanubrutinib and obinutuzumab; v) Response rate in
relationship to molecular and genetic prognostic factors; vi) Immunological recovery;
vii) Overall survival (OS); viii) Biomarkers for response.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Adult patients with previously untreated CLL defined following IWCLL criteria
(Hallek, 2018).
2. Must understand and voluntarily sign an informed consent form.
3. Age ≥ 18 years at the time of signing the informed consent form and must be able to
adhere to the study visit schedule and other protocol requirements.
4. Must have a documented diagnosis of CLL or SLL [IWCLL guidelines for diagnosis and
treatment of CLL (Hallek, 2018)] meeting at least one of the following criteria:
- Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia and/or thrombocytopenia.
- Massive (i.e. ≥6 cm below the left costal margin) or progressive or symptomatic
splenomegaly.
- Massive nodes (i.e. ≥10 cm in longest diameter) or progressive or symptomatic
lymphadenopathy.
- Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or
lymphocyte doubling time (LDT) of less than 6 months.
- A minimum of any one of the following disease-related symptoms: unintentional
weight loss ≥ 10% within the previous 6 months, significant fatigue (i.e., ECOG
PS 2 or worse; cannot work or unable to perform usual activities), fevers of
greater than 38.0°C for 2 or more weeks without other evidence of infection, or
night sweats for more than 1 month without evidence of infection.
- Autoimmune complications including anemia or thrombocytopenia poorly responsive
to corticosteroids.
- Symptomatic or functional extranodal involvement (eg, skin, kidney, lung,
spine).
5. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of
≤2.
6. Female patients of childbearing potential must practice highly effective methods of
contraception initiated prior to first dose of study drug, for the duration of the
study, and for ≥ 90 days after the last dose of zanubrutinib and 18 months after
last dose of obinutuzumab.
Male patients are eligible if vasectomized or if they agree to the use of barrier
contraception with other applicable highly effective methods described below during
the study treatment period and for ≥ 90 days after the last dose of zanubrutinib and
18 months after last dose of obinutuzumab.
A woman is considered of childbearing potential, ie, fertile, following menarche and
until becoming postmenopausal unless permanently sterile. Permanent sterilization
methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
Contraception methods include the following:
- Combined (estrogen- and progestogen- containing) hormonal contraception
associated with the inhibition of ovulation - Oral, intravaginal, or
transdermal.
- Progestogen-only hormonal contraception associated with the inhibition of
ovulation - Oral, injectable, implantable.
- An intrauterine device.
- Intrauterine hormone-releasing system.
- Bilateral tubal occlusion.
- Vasectomized partner (provided that the vasectomized partner is the sole sexual
partner of the woman of childbearing potential study participant and that the
vasectomized partner has received medical assessment of surgical success).
- Sexual abstinence (defined as refraining from heterosexual intercourse during
the entire period of risk associated with the study treatment, starting the day
prior to first dose of study drug, for the duration of the study, and for ≥ 90
days after the last dose of zanubrutinib or ibrutinib. Total sexual abstinence
should only be used as a contraceptive method if it is in line with the
patients' usual and preferred lifestyle. Periodic abstinence (eg, calendar,
ovulation, symptothermal, post-ovulation methods), declaration of abstinence
for the duration of exposure to investigational medicinal product, and
withdrawal are not acceptable methods of contraception.
Of note, barrier contraception (including male and female condoms with or without
spermicide) is not considered a highly effective method of contraception, and, if
used, this method must be used in combination with another acceptable method listed
above.
If patient is using hormonal contraceptives such as birth control pills or devices,
a barrier method of contraception (eg, condoms) must also be used.
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. A high follicle-stimulating hormone level in the postmenopausal range
may be used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy. However, in the absence of 12 months
of amenorrhea, a single follicle-stimulating hormone measurement is insufficient.
7. Female subjects of childbearing potential must have a negative pregnancy test at
screening. Females of child bearing potential are defined as sexually mature women
without prior hysterectomy or who have had any evidence of menses in the past 12
months. However, women who have been amenorrheic for 12 or more months are still
considered to be of childbearing potential if the amenorrhea is possibly due to
other causes, including prior chemotherapy, anti-estrogens, or ovarian suppression.
Exclusion Criteria:
1. Prior treatment for CLL.
2. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C
Virus (HCV) infection. Subjects who are hepatitis B core antibody (anti-HBc)
positive and who are surface antigen negative could be eligible if they have an
undetectable HBV DNA (negative polymerase chain reaction (PCR) <20 IU). Those who
are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be
excluded. Subjects who are hepatitis C antibody positive will need to have a
negative PCR result. Those who are hepatitis C PCR positive will be excluded.
Per published guidelines (NCCN 2012) or institutional guidelines, patients should be
closely monitored for hepatitis B reactivation. Obtaining repeated hepatitis B PCR
every 3 months during treatment and for the 12 months after last dose of study drug
according to usual clinical practice in order to monitor for reactivation of
hepatitis B is recommended.
3. Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) ≤30 mL/min/1.73m2.
4. Absolute neutrophil count (ANC) < 1.0 X 109/L.
5. Platelet count < 75 X 109/L, except for patients with bone marrow involvement by CLL
in which case the platelet count must be ≥ 30 X 109/L.
6. Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase
(SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT)
>2.5 x upper limit of normal (ULN).
7. Serum total bilirubin > 1.5 x ULN, except in cases of Gilbert's syndrome.
8. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x ULN.
9. Active bleeding, history of bleeding diathesis (eg, haemophilia or von Willebrand
disease).
10. Unable to swallow capsules, or has disease significantly affecting gastrointestinal
function that would limit absorption of oral medication.
11. Currently active, clinically significant cardiovascular disease or a history of
myocardial infarction within 3 months prior to enrollment. Exception: Subjects with
controlled, asymptomatic atrial fibrillation during screening can enrol on study.
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
13. Systemic infection that has not resolved prior to initiating study treatment in
spite of adequate anti-infective therapy.
14. Pregnant or lactating females.
15. Participation in any clinical study or having taken any investigational therapy
within 28 days prior to initiating study therapy.
16. Central nervous system (CNS) involvement as documented by spinal fluid cytology or
imaging.
17. Prior history of malignancies, other than CLL, unless the patient has been free of
the disease for ≥ 3 years.
Exceptions include the following:
- Basal cell carcinoma of the skin
- Squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
- Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
18. Presence of autoimmune haemolytic anaemia or autoimmune thrombocytopenia.
19. Major surgery within the last 28 days prior to registration.
20. History of stroke or intracranial haemorrhage within 6 months prior to enrollment.
21. Requires treatment with strong CYP3A4/5 Inhibitors.
22. Known history of drug-specific hypersensitivity or anaphylaxis to study drug
(including active product or excipient components).
23. Any life-threatening illness, medical condition, or organ system dysfunction which,
in the Investigator's opinion, could compromise the subject's safety, interfere with
the absorption or metabolism of zanubrutinib, or put the study outcomes at undue
risk.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
H. Vall d'Hebron
Address:
City:
Barcelona
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Pau Abrisqueta
Start date:
September 2, 2024
Completion date:
May 31, 2032
Lead sponsor:
Agency:
PETHEMA Foundation
Agency class:
Other
Source:
PETHEMA Foundation
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06544785
