Evaluation of Zanubrutinib and Obinutuzumab Efficacy in Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Patients
- Trial ID
- 2023-504647-14-00
- Protocol
- GELLC-10-ZANUBIO
- Sponsor
- Fundacion PETHEMA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the rate of **complete remission (CR)** with undetectable minimal residual disease (uMRD) achieved with the combination of **zanubrutinib** and **obinutuzumab** in patients with previously untreated **Chronic Lymphocytic Leukemia (CLL)** or **Small Lymphocytic Lymphoma (SLL)**. This comparison will be made between two different administration schedules of obinutuzumab, either starting at cycle 2 or at 12 months. The clinical relevance of this objective lies in determining the optimal treatment schedule that maximizes remission rates, which is crucial for improving patient outcomes in CLL and SLL.
Secondary objectives include further assessment of the efficacy and safety of the combination therapy with two different administration schedules of obinutuzumab through the following outcome measures:
- Overall response rate (ORR), including Complete Remission (CR), CR with incomplete marrow recovery (CRi), Partial Remission (PR), and partial response with lymphocytosis.
- Minimal residual disease (MRD) analysis by flow cytometry and molecular biology.
- Duration of response and Progression-free survival (PFS), defined as the time from randomization until symptomatic disease progression or death by any cause.
- Overall survival (OS), measured as the time between the day of randomization to death from any cause.
- Immunological recovery.
- Safety assessment, including the type, frequency, and severity of adverse events (AEs) and their relationship to zanubrutinib or the combination of zanubrutinib and obinutuzumab. This includes the evaluation of infusion-related reactions (IRR) and tumor lysis syndrome (TLS), with analysis according to the two different schedules of administration of obinutuzumab.
- Biomarkers for response.
Participants
The clinical trial involves participants diagnosed with **Chronic Lymphocytic Leukemia (CLL)** or **Small Lymphocytic Lymphoma (SLL)**. The study population includes both male and female adults aged 18 years and older, with no specific upper age limit mentioned. Participants are required to have a documented diagnosis of CLL or SLL, as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, and must be treatment-naïve. The trial does not include vulnerable populations. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The sponsor has not provided the total number of participants involved in the trial. Lifestyle considerations such as diet and physical activity are not specified, but female participants of childbearing potential must adhere to highly effective contraception methods during and after the study. The selection criteria ensure that participants can adhere to the study visit schedule and other protocol requirements.
Plans and Procedures
The clinical trial is a **randomized**, open-label, phase 2 study designed to evaluate the efficacy and safety of **zanubrutinib** in combination with **obinutuzumab** in patients with previously untreated **Chronic Lymphocytic Leukemia (CLL)** or **Small Lymphocytic Lymphoma (SLL)**. The primary objective is to compare the rate of complete remission with undetectable minimal residual disease obtained with the combination therapy, with two different schedules of administration of obinutuzumab. The trial is expected to commence recruitment on September 16, 2024, and conclude by September 15, 2031.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and performance status. The trial will include regular follow-up visits to monitor treatment response and safety, with assessments of primary and secondary endpoints such as overall response rate, progression-free survival, and overall survival. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement is up to 20 months, depending on the treatment schedule. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Participants will receive **zanubrutinib** orally and **obinutuzumab** via intravenous infusion, with the maximum daily doses being 320 mg and 1000 mg, respectively. The study aims to provide insights into the potential predictive biomarkers of response and mechanisms of resistance in patients with CLL or SLL.
Treatment
The clinical trial involves the administration of **Gazyvaro**, a concentrate for solution for infusion, containing the active substance **obinutuzumab**. This pharmaceutical form is specifically designed for intravenous infusion. The maximum daily dose of Gazyvaro is 1,000 mg, with a total maximum dose of 1,000 mg per treatment cycle. The treatment period for Gazyvaro is set at a maximum of 5 cycles. The administration schedule of obinutuzumab is being evaluated in two different regimens: starting at cycle 2 or after 12 months. The product is manufactured by Roche Registration GmbH and is authorized under the marketing authorization number EU/1/14/937/001.
In addition to Gazyvaro, the trial also includes the administration of **Zanubrutinib**, a **BTK inhibitor** in capsule form. The active substance in Zanubrutinib is **zanubrutinib**, and it is administered orally. The maximum daily dose for Zanubrutinib is 320 mg, with a total maximum dose of 320 mg per treatment cycle. The treatment period for Zanubrutinib extends up to 20 cycles. This product is developed by BeiGene and is identified by the sponsor product code BGB-3111. The trial aims to assess the efficacy and safety of the combination of zanubrutinib and obinutuzumab in patients with previously untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **complete response rate (CRR)** with undetectable minimal residual disease (uMRD) in patients with previously untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). This primary endpoint will be evaluated to determine the effectiveness of the combination of zanubrutinib and obinutuzumab, with two different schedules of administration for obinutuzumab.
Secondary endpoints include the overall response rate (ORR), which encompasses partial response with lymphocytosis, progression-free survival (PFS), overall survival (OS), and immunological recovery. Safety assessments will focus on the type, frequency, and severity of adverse events (AEs) and their relationship to zanubrutinib or the combination therapy, including the evaluation of tumor lysis syndrome. Additionally, potential predictive biomarkers of response and mechanisms of resistance will be explored at baseline, cycle 20, and at progression.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients with treatment-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). 1. Adult patients with previously untreated CLL defined following IWCLL criteria.
- Must understand and voluntarily sign an informed consent form.
- 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.
- Must have a documented diagnosis of CLL or SLL [IWCLL guidelines for diagnosis and treatment of CLL] 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).
- Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.
- 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.
- 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
- Prior treatment for CLL.
- 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.
- Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) ≤30 mL/min/1.73m2
- Absolute neutrophil count (ANC) < 1.0 X 109/L.
- 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.
- 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).
- Serum total bilirubin > 1.5 x ULN, except in cases of Gilbert’s syndrome.
- Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x ULN.
- Active bleeding, history of bleeding diathesis (eg, haemophilia or von Willebrand disease).
- Unable to swallow capsules, or has disease significantly affecting gastrointestinal function that would limit absorption of oral medication.
- 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.
- Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
- Systemic infection that has not resolved prior to initiating study treatment in spite of adequate anti-infective therapy.
- Pregnant or lactating females.
- Participation in any clinical study or having taken any investigational therapy within 28 days prior to initiating study therapy.
- Central nervous system (CNS) involvement as documented by spinal fluid cytology or imaging.
- 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)
- Presence of autoimmune haemolytic anaemia or autoimmune thrombocytopenia.
- Major surgery within the last 28 days prior to registration.
- History of stroke or intracranial haemorrhage within 6 months prior to enrollment.
- Requires treatment with strong CYP3A4/5 Inhibitors.
- Known history of drug-specific hypersensitivity or anaphylaxis to study drug (including active product or excipient components).
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 16 Sept 2024 | 106 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Zanubrutinib | Test | CAPSULE | ORAL | 320 | 20 | PRD4470763 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1000 | 5 | PRD1753415 |