Tailored Ibrutinib and Venetoclax Regimens in Untreated Chronic Lymphocytic Leukemia: A Multicohort Efficacy Evaluation
- Trial ID
- 2023-504044-34-00
- Protocol
- 54179060CLL2032
- Sponsor
- Janssen Cilag International
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of Ibrutinib plus Venetoclax (I+V) and Ibrutinib monotherapy regimens in patients with previously untreated **Chronic Lymphocytic Leukemia**. The study employs a tailored treatment approach where the dosing of **Ibrutinib** is either proactively reduced or reactively modified in response to adverse events, compared with historical controls from clinical trials of Ibrutinib monotherapy and I+V. This objective is clinically relevant as it aims to optimize treatment regimens, potentially improving patient outcomes and minimizing adverse effects in this patient population.
Participants
The clinical trial involves a total of **135 participants** diagnosed with **untreated Chronic Lymphocytic Leukemia (CLL)**. The study population includes both male and female subjects, with age categories ranging from adults to the elderly. Participants were selected based on specific inclusion criteria, including a diagnosis of CLL/SLL that meets iwCLL diagnostic criteria and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 for I+V cohorts and 0-2 for ibrutinib monotherapy cohorts. The trial also considers individuals with active disease requiring treatment as per iwCLL criteria, and those with adequate hematologic, hepatic, and renal function. The trial population includes vulnerable groups, and lifestyle factors such as diet and physical activity are not specified. The selection process ensures that participants have adequate organ function and meet the necessary health criteria to participate in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of tailored treatment regimens for patients with previously untreated **chronic lymphocytic leukemia** (CLL). The study employs a randomized, double-blind, controlled design to compare the outcomes of ibrutinib monotherapy and a combination regimen of ibrutinib and venetoclax (I+V) against historical controls. The trial is set to commence recruitment on November 28, 2023, and is expected to conclude by November 16, 2028, with a total duration of approximately five years. Participants will be involved in the study for a maximum treatment period of 420 days, depending on the cohort assignment.
Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as diagnosis of CLL/SLL, ECOG performance status, and adequate organ function. Following enrollment, participants will undergo regular follow-up visits to assess treatment response, monitor adverse events, and adjust dosing as necessary. The end-of-study visit will evaluate the overall response rate (ORR) as the primary endpoint, assessed by investigator evaluation. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the protocol, or withdraw consent.
The trial will utilize **ibrutinib** and **venetoclax**, administered orally in the form of hard capsules and film-coated tablets, respectively. The maximum daily dose for ibrutinib is 420 mg, while venetoclax is capped at 400 mg. The study aims to customize treatment regimens by either proactively reducing or reactively modifying ibrutinib dosing in response to adverse events, thereby optimizing therapeutic outcomes. The trial's primary objective is to determine the best ORR, with secondary endpoints focusing on safety and tolerability. Participants will be closely monitored throughout the study to ensure adherence to the protocol and to address any emerging safety concerns promptly.
Treatment
The clinical trial involves the administration of **venetoclax**, marketed under the name Venclyxto, in various dosages as part of the experimental treatment regimen. Venclyxto is available in film-coated tablet form with dosages of 10 mg, 50 mg, and 100 mg. The active substance, venetoclax, is a chemical compound also known by synonyms such as ABT-199 and GDC-0199. The maximum daily dose for venetoclax is 400 mg, administered orally. The treatment period for venetoclax is up to 366 days. The tablets are manufactured by AbbVie Deutschland GmbH & Co. KG and are not formulated for pediatric use.
Another experimental medication used in the trial is **ibrutinib**, available under the product name IMBRUVICA, in the form of 140 mg hard capsules. Ibrutinib is a chemical compound, and the maximum daily dose is 420 mg, administered orally. The treatment period for ibrutinib extends up to 420 days. IMBRUVICA is produced by Janssen-Cilag International NV and is not intended for pediatric formulations. Additionally, a product coded as JNJ-54179060, containing ibrutinib, is also utilized in the trial in capsule form, with similar dosing and administration guidelines as IMBRUVICA.
The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial aims to evaluate the efficacy of tailored treatment approaches involving venetoclax and ibrutinib in patients with previously untreated chronic lymphocytic leukemia.
Efficacy
The efficacy of the clinical trial will be assessed using the primary endpoint of Best Overall Response Rate (ORR) as determined by investigator assessment. This endpoint will evaluate the effectiveness of the treatment regimens involving **ibrutinib** and the combination of ibrutinib with venetoclax (I+V) in patients with previously untreated Chronic Lymphocytic Leukemia (CLL). The trial aims to compare these regimens with historical controls of ibrutinib monotherapy and I+V, utilizing a tailored treatment approach where the dosing of ibrutinib is adjusted either proactively or reactively in response to adverse events (AEs).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Diagnosis of CLL/SLL that meets iwCLL diagnostic criteria
- For I+V cohorts: ECOG performance status of 0-1. For ibrutinib monotherapy cohorts: ECOG performance status of 0-2
- Active disease meeting at least 1 of the following iwCLL criteria for requiring treatment: a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. b. Massive (ie, ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly. c. Massive nodes (ie, ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy. d. Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or LDT <6 months. e. Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids. f. Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine). g. Disease-related symptoms as defined by any of the following: i. Unintentional weight loss ≥10% within the previous 6 months. ii. Significant fatigue (ie, ECOG performance scale 2 or worse; cannot work or unable to perform usual activities). iii. Fevers ≥100.5°F or 38.0°C for ≥2 weeks without evidence of infection. iv. Night sweats for ≥1 month without evidence of infection.
- Adequate hematologic function independent of transfusion and growth factor support for at least 7 days (except for pegylated G-CSF [pegfilgrastim] and darbepoetin, which require at least 14 days) prior to screening laboratory assessment defined as: a. ANC >750/μL independent of growth factor support; b. Platelet count >50,000/μL independent of transfusion support for at least 7 days prior to enrollment; c. Hemoglobin >8.0 g/dL independent of transfusion support for >7 days prior to enrollment
- Adequate hepatic function, defined as: a. Serum AST or ALT ≤3.0×ULN; b. Bilirubin ≤1.5×ULN (unless bilirubin rise is due to congenital nonhemolytic hyperbilirubinemias or of non-hepatic origin); c. Prothrombin time/international normal ratio <1.5×ULN and activated partial thromboplastin time <1.5×ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder)
- Adequate renal function, defined as follows (using the Cockcroft-Gault equation): a. For I+V cohorts: i. In participants aged <75 years at enrollment, CrCl ≥45 mL/min; ii. In participants aged ≥75 years at enrollment, CrCl ≥60 mL/min. b. For ibrutinib monotherapy cohorts, CrCl ≥45 mL/min
Exclusion Criteria
- Medical history of: a. Other malignancies, except: i. Any malignancy that was not progressing nor requiring treatment change in the last 12 months. ii. Malignancies treated within the last 12 months and considered at very low risk for recurrence: 1. Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade, <3 cm, no CIS). 2. Skin cancer (non-melanoma or melanoma). 3. Non-invasive cervical cancer. 4. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving antihormonal agents. 5. Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (RP/RT/focal treatment). iii. Other malignancy that is considered at minimal risk of recurrence. b. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, such as those participants with a declining hemoglobin level or platelet count secondary to autoimmune destruction within the 4 weeks prior to first dose of study treatment, or the need for prednisone >20 mg daily (or corticosteroid equivalent) to treat or control the autoimmune disease. c. Recent infection requiring systemic treatment that is ongoing or was completed ≤14 days before the first dose of study treatment, or any uncontrolled active systemic infection. d. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia). e. Stroke or intracranial hemorrhage within 6 months prior to enrollment. f. Difficult to control hypertension (defined as requiring ≥3 hypertensive medications) or screening systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg. For participants whose screening blood pressure exceeds a systolic blood pressure of 160 mmHg or a diastolic blood pressure of 100 mmHg, the investigator should review and manage the participant appropriately according to individual practice. The participant may be rescreened if it can be demonstrated that the blood pressure reading was a single isolated elevation or is subsequently controlled and stable. g. History of myocardial infarction, ventricular arrhythmia, unstable angina, or acute coronary syndrome within 12 months prior to enrollment (if >1 year, cardiology consultation is recommended prior to study enrollment)
- Known or suspected Richter’s transformation or CNS involvement
- Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class II, III, or IV congestive heart failure as defined by the New York Heart Association Functional Classification (see Section 10.8). For participants who in the investigator’s opinion are considered to have a significant cardiac risk at baseline, the investigator should consider pursuing a cardiology evaluation before screening. It is the investigator’s responsibility to assess the risks and benefits of subsequent study enrolment
- Participant received prior systemic anticancer therapy (including but not limited to chemotherapy, targeted therapy, immunomodulating therapy, radiotherapy, and/or monoclonal antibody) for treatment of CLL or SLL
- Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise their wellbeing) or that could prevent, limit, or confound the protocol-specified assessments
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 28 Nov 2023 | 60 |
 France | Recruiting | 28 Nov 2023 | 15 |
 Hungary | Recruiting | 28 Nov 2023 | 21 |
 Italy | Recruiting | 28 Nov 2023 | 60 |
 Poland | Recruiting | 28 Nov 2023 | 30 |
 Spain | Recruiting | 28 Nov 2023 | 27 |
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 |
|---|---|---|---|---|---|---|
Venclyxto 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 400 | 366 | PRD6353834 |
IMBRUVICA 140 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 420 | 420 | PRD1729393 |
Venclyxto 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 400 | 366 | PRD6353842 |
Venclyxto 10 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 400 | 366 | PRD6353822 |
Venclyxto 50 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 400 | 366 | PRD6353830 |
JNJ-54179060 | Test | CAPSULE, HARD | ORAL USE | 420 | 420 | PRD10333688 |