Phase 3 Study of Lisaftoclax (APG-2575) and Acalabrutinib in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Patients
- Trial ID
- 2023-508005-24-00
- Protocol
- APG2575CG301
- Sponsor
- Ascentage Pharma Group Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **progression-free survival (PFS)** of lisaftoclax in combination with acalabrutinib compared to acalabrutinib monotherapy in patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) who have been previously treated with acalabrutinib. This is determined by an independent radiological review committee using the iwCLL guidelines. The clinical relevance of this objective lies in its potential to improve treatment outcomes by extending the duration patients remain free from disease progression, which is a critical measure of treatment efficacy in oncology.
Secondary objectives include: - Evaluating overall survival (OS) of lisaftoclax in combination with acalabrutinib versus acalabrutinib alone. - Determining the efficacy of the combination therapy compared to acalabrutinib monotherapy through additional outcome measures such as PFS by investigators, overall response rate (ORR), complete response/complete response with incomplete hematologic recovery (CR/CRi) rate, duration of response (DoR), and undetectable minimal residual disease (uMRD) rate. - Evaluating the safety profile of the combination therapy versus acalabrutinib alone. - Characterizing the population pharmacokinetics of lisaftoclax. - Assessing Patient-Reported Outcome (PRO) measures based on the EORTC QLQ-C30. - Evaluating Health Economics Outcomes Research (HEOR) measures based on the Europol 5 Dimension (EQ-5D-5L).
Participants
The clinical trial involves a total of **223 participants** diagnosed with **Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their previous treatment with acalabrutinib monotherapy for at least 12 months, with a stable disease or partial response accompanied by specific baseline risk factors. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of self-care. Participants are required to have adequate bone marrow, renal, and liver function. The study population is characterized by a diverse range of health statuses, with the inclusion of vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **lisaftoclax** in combination with **acalabrutinib** compared to acalabrutinib monotherapy in patients with **Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)**. The primary objective is to assess progression-free survival (PFS) as determined by an independent radiological review committee using the iwCLL guidelines. The trial is expected to commence recruitment on June 1, 2024, and conclude by May 31, 2031, with a maximum treatment period of 76 weeks for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, previous treatment history, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, including assessments of adverse events and laboratory results. The end-of-study visit will evaluate the overall response rate and other secondary endpoints, such as overall survival and duration of response.
The expected length of participant involvement is up to 76 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will also assess safety endpoints, including the incidence of adverse events and pharmacokinetics, alongside patient-reported outcomes and health economics measures. The study aims to provide comprehensive data on the efficacy and safety of the combination therapy in a previously treated CLL/SLL population.
Treatment
The clinical trial involves the administration of **acalabrutinib**, marketed as Calquence, which is available in two pharmaceutical forms: film-coated tablets and hard capsules. Each form contains 100 mg of the active substance. Acalabrutinib is a highly selective Bruton’s tyrosine kinase inhibitor, used as an oral, targeted treatment for Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL). The maximum daily dose is 200 mg, administered orally, with a treatment period extending up to 76 weeks. The medication is provided by AstraZeneca AB and is authorized for use in the European Union.
Another experimental medication used in the trial is **lisaftoclax**, also known by its sponsor product code APG-2575. Lisaftoclax is a small molecule antagonist of Bcl-2, provided in tablet form. The maximum daily dose for lisaftoclax is 400 mg, administered orally, with a treatment period of up to 76 weeks. This medication is developed by Ascentage Pharma Group Inc. and is currently in the investigational phase, with no marketing authorization status.
Both medications are administered orally, and participant compliance is monitored throughout the trial. The study aims to evaluate the progression-free survival of lisaftoclax in combination with acalabrutinib compared to acalabrutinib monotherapy in patients with CLL/SLL who have been previously treated with acalabrutinib. The trial does not include any non-experimental treatments such as placebo or standard-of-care therapy as comparators.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**. This will be determined by an independent radiological review committee (IRC) using the iwCLL guidelines. PFS is defined as the time from randomization to the first occurrence of disease progression, relapse, or death from any cause, whichever occurs first. Secondary endpoints include overall survival (OS), which is the time from randomization to death from any cause, and other measures such as overall response rate (ORR), duration of response, and the proportion of patients achieving complete response (CR) or complete response with incomplete recovery (CRi).
Additional secondary efficacy endpoints involve the assessment of the proportion of patients with undetectable minimal residual disease. Safety endpoints will include the incidence and severity of adverse events, serious adverse events, and changes in laboratory results during and within 30 days of treatment discontinuation. Pharmacokinetics will be analyzed through population PK analysis. Patient-reported outcomes will be evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) and the associated CLL module (QLQ-CLL17). Health Economics and Outcomes Research (HEOR) will be assessed using the EuroQoL 5-Dimension (EQ-5D-5L) questionnaire.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Aged ≥ 18 years.
- Patients that have documented CLL/SLL who meet iwCLL 2018 criteria for CLL treatment guidelines are eligible. • Received a BTKi (acalabrutinib, ibrutinib, or zanubrutinib) monotherapy as 1st, 2nd, or 3rd line therapy for ≥ 12 months and have best response as either a or b: a. Stable disease b. PR with any of the following baseline risk factors: • Lymph node(s) diameter ≥ 2.5 cm, • ALC ≥ 25x 109 /L • Have ≥ 1 high-risk factor(s) (del17p/p53mut, unmutated IGHV, complex karyotype ≥ 5 factors (≥ 3 chromosomal abnormalities and ≥ 1 biological/structural aberrations).
- ECOG performance status 0-2.
- Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of randomization as follows: • Absolute neutrophil count ≥ 1.0 × 109/L • Platelet counts ≥ 75 × 109/L; in cases of thrombocytopenia • Total hemoglobin ≥ 9 g/dL -.
- Adequate renal function • Creatinine clearance must be > 50 ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 – age) x actual bodyweight) / (72 x creatinine), for women x 0. 85) or an equally accurate method.
- Adequate liver function as indicated by: • Total bilirubin ≤ 1.5 x ULN, except patients with known Gilbert’s Syndrome • Aspartate aminotransferase (AST) ≤ 2.5 x the institutional ULN value • Alanine aminotransferase (ALT) ≤ 2.5 x the institutional ULN value, • International Normalized Ratio (INR), Prothrombin Time (PT) or Activated Partial Thromboplastin time (APTT) ≤ 1.5 × ULN.
- Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
Exclusion Criteria
- Achieved complete response (CR) or CRi status or disease progression while on BTKi (acalabrutinib, ibrutinib, zanubrutinib) monotherapy prior to study entry.
- Transformation of CLL to Richter’s condition.
- Prior treatment with venetoclax or other Bcl-2 inhibitors.
- An individual organ/system impairment score of 4 as assessed by the cumulative illness rating scale (CIRS) definition limiting the ability to receive the study treatment, or any other life-threatening illness, medical condition, or organ system dysfunction that, in the investigator´s opinion, could compromise the patients’ safety or interfere with the absorption or metabolism of the study drugs (e.g., inability to swallow tablets or impaired resorption in the gastrointestinal tract).
- Patients receiving acalabrutinib capsule-based therapy (not tablet) who require treatment with proton pump inhibitors (e.g, omeprazole esomeprazole, lansoprazole etc,) at study entry. (Patients receiving proton pump inhibitors who switch to H2 receptors antagonists or antacids are eligible for enrollment).
- Patients who require or are receiving anticoagulation therapy with warfarin or equivalent vitamin K antagonists within 7 days of first dose of the study drug(s).
- Patients who are pregnant or breastfeeding.
- Has received the following within 7 days prior to the first dose of study drug: • Steroid therapy at a dose greater than prednisone 20 mg daily (or equivalent) for anti-neoplastic intent. • CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin or potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John’s wort.
- Radiation within 14 days of study entry.
- Continuance of toxicities due to prior radiotherapy or chemotherapy agents that have not recovered to ≤ grade 1 or baseline, except alopecia or neuropathy.
- Failure to recover, as judged by the investigator, from prior surgical procedures. Patients with active wound healing, patients who have had major surgery within 28 days and minor surgery such as a biopsy within 14 days from first dose of study drug.
- QTcF interval＞ 480ms or other remarkable abnormality of ECG, including second-degree type II atrioventricular block, third-degree atrioventricular block, or bradycardia (ventricular rate consistently less than 50 beats per minute).
- Underlying clinically significant cardiovascular disease such as: symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening or any cardiovascular disability status of New York Heart Association Class ≥ 2.
- Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
- Uncontrolled medical condition (e.g., diabetes).
- Known to have central nervous system (CNS) involvement.
- Prior malignancy within 2 years of treatment that required radiotherapy, or systemic therapy.
- Patients treated with strong CYP3A4 inhibitors/inducers (patients can be washed out allowing 5 half-lives prior to study treatment and/or switched to non-prohibited drug.
- History of stroke or intracranial hemorrhage within 3 months prior to registration for study screening or known bleeding disorders.
- Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
- Vaccination with live vaccines within 14 days prior to screening (30 days for patients in Czech Republic).
- Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV, HCV infection or active COVID-19. (Patients who have received COVID-19 vaccination will be considered as eligible for the study.) (For patients from the Czech Republic, HBV, HCV and HIV testing is mandated at screening for these criteria to be met).
- Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly).
- Fertile men or women of childbearing potential unless: surgically sterile or ≥ 2 years after the onset of menopause or willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 3 months after the end of study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 01 Jun 2024 | 15 |
 Bulgaria | Recruiting | 01 Jun 2024 | 15 |
 Czechia | Recruiting | 01 Jun 2024 | 9 |
 France | Recruiting | 01 Jun 2024 | 35 |
 Germany | Recruiting | 01 Jun 2024 | 20 |
 Hungary | Recruiting | 01 Jun 2024 | 10 |
 Italy | Recruiting | 01 Jun 2024 | 45 |
 Poland | Recruiting | 01 Jun 2024 | 35 |
 Romania | Recruiting | 01 Jun 2024 | 20 |
 Slovakia | Recruiting | 01 Jun 2024 | 17 |
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 |
|---|---|---|---|---|---|---|
BRUKINSA 80 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 160 | 76 | PRD9341336 |
IMBRUVICA 140 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 420 | 76 | PRD7294190 |
Lisaftoclax | Test | TABLET | ORAL USE | 400 | 76 | PRD8842215 |
IMBRUVICA 140 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 420 | 76 | PRD1729393 |
Calquence 100 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 200 | 76 | PRD8485702 |
Lisaftoclax | Test | TABLET | ORAL USE | 400 | 76 | PRD8842216 |
IMBRUVICA 140 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 420 | 76 | PRD1729387 |
Calquence 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 200 | 76 | PRD10242587 |
IMBRUVICA 140 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 420 | 76 | PRD7294186 |
Calquence 100 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 200 | 76 | PRD8485701 |