A Phase 3, Open-Label, Randomized, Multicenter Study to Evaluate Anti-tumor Efficacy of DZD8586 versus Investigator's Choice in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
- Trial ID
- 2025-522669-32-00
- Protocol
- DZ2024B0002
Trial statistics
Diseases & Conditions
Objectives
This Phase 3, open-label, randomized, multicenter study evaluates patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. The primary objective is to evaluate the anti-tumor efficacy of DZD8586 compared to investigator's choice. This comparison is clinically relevant for determining whether DZD8586, a LYN/BTK dual inhibitor, provides superior therapeutic benefit over existing standard treatment options in this patient population with disease that has relapsed or proven refractory to prior therapies.
The secondary objectives include:
• To evaluate the anti-tumor efficacy of the two treatment arms using other endpoints.
• To evaluate the safety and tolerability of the two treatment arms.
• To evaluate pharmacokinetics of DZD8586 and its metabolite DZ4581 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.
Participants
This clinical trial enrolled a total of **195 participants** diagnosed with **relapsed or refractory chronic lymphocytic leukemia** or **small lymphocytic lymphoma**. The study population included both **male and female patients** aged **18 years and older**. Participants were required to have an **Eastern Cooperative Oncology Group performance status** of 0 to 2, indicating relatively preserved functional capacity. The trial specifically recruited patients who had previously experienced relapse, refractoriness, or intolerance during or after treatment with a **BTK inhibitor**, and who had also been previously treated with a **BCL-2 inhibitor** according to local clinical practice. Participants were required to demonstrate adequate **bone marrow** hematopoietic reserve and organ function, including specified minimum levels of **absolute neutrophil count**, **platelet count**, and acceptable liver and kidney function parameters. Patients with **small lymphocytic lymphoma** were required to have at least one measurable lesion. Female participants of childbearing potential were required to use adequate contraception methods throughout the study period and beyond, while male participants were similarly required to use barrier contraception if their partners were women of childbearing potential. All participants were expected to have a life expectancy of at least 3 months and meet clinical criteria for treatment based on disease burden and progression indicators.
Plans and Procedures
This is a Phase 3, open-label, randomized, multicenter clinical trial evaluating the anti-tumor efficacy of Birelentinib (DZD8586) compared to investigator's choice in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. The investigational medicinal product Birelentinib is a LYN/BTK dual inhibitor administered orally as film-coated tablets at a maximum daily dose of 50 mg. The comparator treatments include idelalisib (a protein kinase inhibitor administered orally), bendamustine hydrochloride (an alkylating agent administered via intravenous infusion), and rituximab (a monoclonal antibody administered as solution for infusion). All comparator medicinal products will be relabeled and repackaged prior to use in the trial.
The primary objective of the trial is to evaluate the anti-tumor efficacy of DZD8586 compared to investigator's choice. The primary endpoint is progression-free survival assessed by an Independent Review Committee according to iwCLL 2018 and Lugano 2014 criteria. Secondary endpoints include progression-free survival assessed by investigator, objective response rate, duration of response, overall survival, time to next treatment, and quality of life assessments using EQ-5D-5L and EORTC QLQ-C30 questionnaires. Safety profiles will be evaluated including adverse events, serious adverse events, and events of Grade 3 or higher according to CTCAE v5.0. Plasma concentrations of DZD8586 and its metabolite DZ4581 will be measured along with derived pharmacokinetic parameters.
The maximum treatment period for Birelentinib and idelalisib is 36 months, while bendamustine and rituximab have a maximum treatment period of 24 months. The total maximum dose amounts are 54,750 mg for Birelentinib, 328,500 mg for idelalisib, 840 mg/m² for bendamustine, and 3,875 mg/m² for rituximab. The estimated recruitment start date is December 2025, with an estimated trial end date of November 2028.
Eligible participants must be aged 18 years or older with an ECOG performance status of 0-2 and a life expectancy of at least 3 months. Patients must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma according to iwCLL 2018 criteria and meet criteria for clinical treatment with evidence of disease burden requiring intervention. Participants must have experienced relapse, refractory disease, or intolerance during or after any previous BTK inhibitor treatment. According to local clinical practice in European countries, patients should have been previously treated with a BCL-2 inhibitor. Patients with small lymphocytic lymphoma must have at least one measurable lesion with a longest diameter greater than 1.5 cm for lymph nodes or greater than 1.0 cm for extranodal lesions.
Adequate bone marrow function is required, including absolute neutrophil count of at least 0.75 × 10⁹/L and platelet count of at least 50 × 10⁹/L (or 75 × 10⁹/L if bendamustine plus rituximab is planned as treatment). Additional requirements include adequate coagulation parameters with APTT, PT, and INR not exceeding 1.5 times the upper limit of normal. Hepatic function must be adequate with total bilirubin not exceeding 1.5 times the upper limit of normal (or 3 times in the presence of Gilbert's Syndrome or liver metastasis) and ALT and AST not exceeding 2.5 times the upper limit of normal (or 3 times with liver metastasis). Renal function must demonstrate creatinine clearance of at least 30 mL/min calculated by the Cockcroft-Gault method. Cardiac function must show left ventricular ejection fraction of at least 50% as assessed by echocardiography.
Female participants of childbearing potential must use adequate contraception methods during the study and for 3 months after the last dose of DZD8586 or idelalisib, 6 months after bendamustine, or 12 months after rituximab, whichever is longer. Acceptable contraception methods include sexual abstinence, tubal ligation, hormonal contraception with low risk of drug interactions (levonorgestrel intrauterine system or medroxyprogesterone injection), copper-banded intrauterine devices, and partner vasectomy. All hormonal contraception methods except abstinence should be used in combination with condoms by male partners. Female participants must have a negative pregnancy test prior to initiation of study treatment and must not breastfeed during the trial. Postmenopausal women are defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatment, or women under 50 years old who have been amenorrhoeic for 12 months with LH and FSH levels in the postmenopausal range. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy is also acceptable. Male participants must use barrier contraception during the study and for 6 months following the last dose of DZD8586, bendamustine, or idelalisib, or 12 months following the last dose of rituximab, whichever is longer. Male participants must avoid sperm donation during this period and should be advised to arrange for freezing of sperm samples prior to the start of study treatment if they wish to father children.
Treatment
The experimental treatment in this clinical trial is **Birelentinib** (also known by the sponsor product code **DZD8586**), which contains the active substance [(2S,5S)-5-{4-amino-5-[4-(2,3-difluorophenoxy)phenyl]imidazo[5,1-f][1,2,4]triazin-7-yl}oxan-2-yl]methanol. Birelentinib is classified as a **LYN/BTK dual inhibitor** with **antineoplastic** activity. The medicinal product is supplied as **film-coated tablets** for **oral administration**. The maximum daily dose is **50 mg** and the maximum total dose over the treatment period is **54,750 mg**. The maximum treatment duration is **36 months**. This investigational medicinal product has not yet received marketing authorization.
The comparator treatments used in this study consist of **idelalisib**, **bendamustine hydrochloride**, and **rituximab**, representing investigator's choice therapy. All comparator medicinal products are sourced from the European Union market and undergo **repackaging and relabeling** by Fisher Clinical, Germany.
**Idelalisib** is marketed under the trade name **Zydelig** and is available in two strengths: **100 mg film-coated tablets** and **150 mg film-coated tablets**. Idelalisib is a **protein kinase inhibitor** belonging to the **antineoplastic agents** class. The medicinal product is administered via the **oral route**. For the 100 mg formulation, the maximum daily dose is **200 mg** with a maximum total dose of **219,000 mg** over a treatment period of up to **36 months**. For the 150 mg formulation, the maximum daily dose is **300 mg** with a maximum total dose of **328,500 mg** over the same treatment duration. The marketing authorization holder is Gilead Sciences Ireland Unlimited Company.
**Bendamustine hydrochloride** is supplied under the trade name **Bendamustin Hikma** as a powder for concentrate for **solution for infusion** at a concentration of **2.5 mg/ml**. This agent is classified as an **alkylating agent** within the **antineoplastic agents** category. Administration is performed via **intravenous infusion**. The maximum daily dose is **70 mg/m²** with a maximum total dose of **840 mg/m²** over a treatment period of up to **24 weeks**. The marketing authorization holder is Hikma Farmacêutica (Portugal), S.A.
**Rituximab** is provided under the trade name **Truxima** as a **500 mg concentrate for solution for infusion**. Rituximab is a **monoclonal antibody** categorized as an **antineoplastic agent**. The medicinal product is administered as a **solution for infusion**. The maximum daily dose is **500 mg/m²** with a maximum total dose of **3,875 mg/m²** over a treatment period of up to **24 weeks**. The marketing authorization holder is Celltrion Healthcare Hungary Kft.
Efficacy
Efficacy will be assessed through multiple parameters measuring disease response and patient outcomes in this clinical trial. The primary efficacy endpoint is progression free survival assessed by Independent Review Committee according to iwCLL 2018 and Lugano 2014 criteria. Secondary efficacy endpoints include progression free survival assessed by investigator, objective response rate and duration of response assessed by both Independent Review Committee and investigator, overall survival, and time to next treatment. Patient-reported outcomes will be evaluated using the EuroQol Group 5-level EQ-5D Questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire to assess quality of life. Safety profiles will be monitored throughout the study, including adverse events, serious adverse events, and Grade 3 or higher adverse events, classified according to Common Terminology Criteria in Adverse Events version 5.0. Pharmacokinetic assessments will include measurement of plasma concentrations of the investigational medicinal product and its metabolite, with derived corresponding pharmacokinetic parameters.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must provide a voluntarily signed and dated written informed consent prior to any study-specific procedures, sampling and analyses.
- Male and female patients must be ≥ 18 years of age when signing the informed consent form.
- Patients must exhibit Eastern Cooperative Oncology Group (ECOG) performance status 0- 2 with no disease deterioration over the previous 2 weeks.
- 4a. Patients diagnosed with CLL/SLL per iwCLL 2018 criteria and meet the following conditions: • Relapsed, refractory or intolerable during or after any previous BTK inhibitor treatment. o The definitions of refractory and relapsed are defined according to the following criteria: a. Refractory: disease progression during treatment or within 6 months after achieving response. b. Relapse: disease progression after achieving partial response (PR) or greater response with prior therapy for at least 6 months. BTK inhibitor therapy is refractory if stable disease (SD) is the best response after treatment with standard dose for 6 months; participants who have disease progression during treatment should be treated with BTK inhibitor for no less than 8 weeks; participants who achieve response after treatment should continue treatment until disease progression or for no less than 6 months after achieving response. o BTK inhibitor intolerant events are defined as the cessation of treatment due to one of the following reasons (drug-related rather than disease-related), despite the best medical treatment, determined by the investigator to be drug-related or potentially drug-related toxicities: a. The same ≥ Grade 2 non-hematological toxicity lasted for ≥ 7 days and recurred twice or more. b. The same ≥ Grade 3 non-hematological toxicity lasted for ≥ 7 days or recurred twice or more (regardless of duration). c. Grade 4 non-hematological toxicity (regardless of duration). d. The same ≥ Grade 3 hematological toxicity lasted for ≥ 7 days and recurred twice or more. e. Grade 3/4 neutropenia with infection or fever (regardless of duration). f. Grade 3 thrombocytopenia with significant clinical bleeding. g. Grade 4 hematological toxicity lasted for ≥ 7 days, or the same Grade 4 hematological toxicity recurred twice or more (regardless of duration). h. Grade 2 or higher, and the risk of adverse events judged by the investigator was high (including but not limited to cardiac and cerebrovascular events, severe bleeding, severe allergy, etc.).
- 4b. • Per the status of the approved drugs in the European countries and clinical practice, patients should have been previously treated with BCL-2 inhibitor according to local clinical practice. • Life expectancy ≥ 3 months. • The patient must meet the criteria for clinical treatment for r/r CLL/SLL based on the iwCLL 2018 guideline, and the investigator judges there’s a need for clinical treatment: o Criteria for initiation of subsequent therapy are met, including persistence of disease burden after front-line therapy and unresolved indications of front-line therapy. o Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. o Massive (i.e., ≥ 6 cm below the left costal margin) or progressive or symptomatic splenomegaly. o Massive nodes (i.e., ≥ 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy. o Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period, or lymphocyte doubling time (LDT) < 6 months. Factors contributing to lymphocytosis other than CLL (e.g., infections, steroid administration) should be excluded. o Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine). o Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids. o Disease-related symptoms as defined by any of the following: unintentional weight loss ≥ 10% within the previous 6 months; significant fatigue (e.g., ECOG performance scale 2 or worse; unable to perform usual activities); fevers ≥ 100.5°F or 38.0°C for 2 or more weeks without evidence of infection; night sweats for ≥ 1 month without evidence of infection.
- SLL patient should have at least one measurable lesion (lymph node longest diameter > 1.5 cm or extranodal lesion longest diameter > 1.0 cm).
- Adequate bone marrow hematopoietic reserve (no blood transfusion and no use of any stimulating factors or erythropoietin within 7 days prior to enrollment visit) and organ function as follows: • Absolute neutrophil count (ANC) ≥ 0.75 × 10^9/L. • Platelets count ≥ 50 × 10^9/L. If BR is planned as the treatment for arm 2, platelets count should ≥ 75 × 10^9/L. • Activated partial thromboplastin time (APTT), prothrombin time (PT), and international normalized ratio (INR) ≤1.5 × ULN. • Total bilirubin ≤ 1.5 × ULN; or ≤ 3 × ULN in the presence of Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastasis (with imaging evidence). • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 3 × ULN in the presence of liver metastasis (with imaging evidence). • Creatinine clearance ≥ 30 mL/min (Cockcroft-Gault method). • Left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiography (ECHO).
- Patients should have the ability to comply with study requirements on study treatment and follow up.
- If the female partner of a male patient is a woman of childbearing potential, the patient should use barrier contraception (e.g., condom) during the study and until 6 months following the last dose of DZD8586/bendamustine/idelalisib or 12 months following the last dose of rituximab, whichever is longer. Male patient should also avoid sperm donation during the study and until 6 months following the last dose of DZD8586/bendamustine/idelalisib or 12 months following the last dose of rituximab, whichever is longer. If male patients wish to father children, they should be advised to arrange for freezing of sperm samples prior to the start of study treatment.
- Female patient should use adequate contraception such as sexual abstinence, tubal ligation, use of hormonal contraception with known low risk of drug interactions (Levonorgestrel intra uterine system [Mirena], medroxyprogesterone injection [Depo Provera]), copperbanded intra-uterine devices, and partner vasectomy during the study and until 3 months after the last dose of DZD8586/idelalisib, 6 months after the last dose of bendamustine, and 12 months after the last dose of rituximab, whichever is longer. All hormonal contraception methods (except abstinence) should be used in combination with the use of condoms by their male sexual partners. Female patient should not breastfeed. Female patient of potential conception should have a negative pregnancy test prior to initiation of study treatment. Female patient may be enrolled if they meet one of the following criteria: • Post-menopausal women defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatment. Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels falling within the post-menopausal range. • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy (excluding tubal ligation).
Exclusion Criteria
- Unresolved adverse reactions greater than Grade 1 (as defined by CTCAE v5.0) prior to the first dose of study treatment (except alopecia, neutropenia, thrombocytopenia, and well-controlled hypertension on medication).
- Richter transformation has been diagnosed or suspected at enrollment.
- Lesions involving the central nervous system.
- History of, or currently taking any of the following treatments (including investigational treatment and study drug): • Prior history of hematopoietic stem cell transplantation, cell therapy, or gene therapy within 90 days prior to the first dose of study treatment. • Chemotherapy and small molecule targeted drug therapy not terminated within 5 half-lives prior to the first dose of study treatment. • Macromolecular drug therapy (e.g., antibody therapy, etc.) not terminated within 28 days prior to the first dose of study treatment. • Any other novel therapy for the current malignancy or therapy not mentioned above should be jointly evaluated by the investigator and the sponsor medical monitor to determine whether the patient is eligible to be enrolled. If the patient undergoes rapid disease progression during the period described above, the investigator must discuss with the sponsor medical monitor to determine whether enrollment is possible. • History of major surgery (excluding vascular access surgery) or significant traumatic injury within 4 weeks prior to the first dose of study treatment or there’s an anticipated need for major surgery after initiation of study treatment. • History of accepting live attenuated vaccines or viral vector vaccines within 4 weeks prior to the first dose of study treatment.
- Currently taking the following medications (or unable to meet the discontinuation duration prior to the first dose of study treatment): • Vitamin K antagonists (or those could not be discontinued within 1 week prior to the first dose of study treatment) • Two or more classes of antiplatelet and anticoagulant drugs are needed to be administered simultaneously. • Known strong CYP3A enzyme inducer or inhibitor, including drugs, herbs or supplements (or those that cannot be discontinued within 1 week prior to the first dose of study treatment. • Antineoplastic traditional medicine that are currently in use and could not be discontinued.
- Active infectious disease, including: HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; HIV: Human Immunodeficiency Virus; CMV: Cytomegalovirus • Other active viral infections (e.g., herpes simplex, herpes zoster, coronavirus, etc.). • The patient requires systemic antimicrobial therapy or interferon treatment. If the patient has a local skin infection and the investigator judges that the patient only requires topical antimicrobial therapy and systemic antimicrobial therapy is not required, it is possible to enroll this patient after discussion with the sponsor medical monitor. • Systemic bacterial or fungal infections (e.g., pulmonary infection, generalized skin infection, etc.) within 14 days prior to the first dose of study treatment and still require treatment.
- Any of the following cardiac abnormity: • Congestive heart failure (CHF) cardiac function > Class II per NYHA classification. • Clinically evident valvular disease, hypertrophic/constrictive cardiomyopathy • Any severe heart rate, conduction, morphological abnormalities on 12-lead electrocardiogram at rest, e.g., complete left bundle branch block, 2/3 degree atrioventricular block, P-R interval > 250 ms. • Ventricular arrhythmia requiring treatment. • Acute myocardial infarction, unstable angina or new angina within 6 months prior to the first dose of study treatment. • Patient with a history of heart transplantation. • QTcF > 480 ms on 12-lead electrocardiogram at rest during screening. • Patient at increased risk of QT prolongation or arrhythmia (e.g., heart failure, hypokalemia, congenital long QT syndrome, taking other drugs leading to QT prolongation); or has a family history of long QT syndrome or a first-degree relative had a history of unexpected sudden death under 40 years of age. • History of thrombotic disorders including pulmonary embolism, deep venous thrombosis, etc., within 6 months prior to the first dose of study treatment. • History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study treatment.
- Patient with refractory nausea and vomiting that cannot be well controlled by supportive therapy, chronic gastrointestinal diseases, dysphagia, or previous surgical resection of intestinal segments that may preclude adequate absorption of the drug.
- History of ongoing drug-induced pneumonitis
- History of confirmed progressive multifocal leukoencephalopathy (PML).
- Patient has been diagnosed with malignancy other than CLL/SLL within the last 2 years. However, if current evidence suggests that the patient has been clinically cured (e.g., radically treated cervical, uterine, basal cell or squamous cell carcinoma in situ or nonmelanoma skin carcinoma in situ) and the investigator believes that the potential benefit of study treatment outweighs the potential risk, the patient may be enrolled.
- Allergic or intolerant to study drug: • History of hypersensitivity to excipients of DZD8586 or other chemical analogues, or prior use of DZD8586. • Prior history of intolerance (defined as toxicity requiring permanent treatment discontinuation) or significant hypersensitivity (excluding manageable infusion-related reactions) to rituximab. • Prior toxic epidermal necrolysis with any drug, known hypersensitivity to any component of idelalisib or vehicle, or prior use of idelalisib if IR treatment is planned for arm 2. • Prior history of intolerance (defined as toxicity requiring permanent treatment discontinuation), other contraindications to bendamustine, or duration of response < 24 months with prior BR treatment if BR treatment is planned for arm 2.
- Patients with severe or poorly controlled systemic diseases as judged by the investigator or other evidence, including poorly controlled active bleeding.
- Personnel involved in the planning and execution of the study (only applicable for staff of sponsor and study site).
- Female patient who are breast feeding or pregnant.
- The patient is unlikely to comply with study procedures, restrictions or requirements as judged by the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 01 Dec 2025 | 29 |
 Poland | Recruiting | 01 Dec 2025 | 26 |
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 |
|---|---|---|---|---|---|---|
Zydelig 150 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 300 | 36 | PRD3430856 |
Truxima 500 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 500 | 24 | PRD4797330 |
Bendamustin Hikma 2,5 mg/ml Pulver für ein Konzentrat zur Herstellung einer Infusionslösung | Comparator | PULVER FÜR EIN KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENIOUS INFUSION | 70 | 24 | PRD8734547 |
Zydelig 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 200 | 36 | PRD3430899 |
Zydelig 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 200 | 36 | PRD1682821 |
Zydelig 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 200 | 36 | PRD3430855 |
Birelentinib | Test | FILM COATED TABLET | ORAL | 50 | 36 | PRD12688286 |
Zydelig 150 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 300 | 36 | PRD3430900 |
Truxima 500 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 500 | 24 | PRD4797331 |
Bendamustin Hikma 2,5 mg/ml Pulver für ein Konzentrat zur Herstellung einer Infusionslösung | Comparator | PULVER FÜR EIN KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENIOUS INFUSION | 70 | 24 | PRD7979465 |