A Phase 3 Study of DZD8586 versus Investigator’s Choice in r/r CLL/SLL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

18 Dec 2025 → ongoing

Decision date (initial)

2025-11-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Dizal (Jiangsu) Pharmaceutical Co., Ltd.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic

To evaluate the anti-tumor efficacy of DZD8586 compared to investigator’s choice.

Secondary objectives 3

1. To evaluate the anti-tumor efficacy of the two treatment arms using other endpoints.
2. To evaluate the safety and tolerability of the two treatment arms.
3. To evaluate pharmacokinetics (PK) of DZD8586 and its metabolite DZ4581 in patients with CLL/SLL.

Conditions and MedDRA coding

Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Patients must provide a voluntarily signed and dated written informed consent prior to any study-specific procedures, sampling and analyses.
2. Male and female patients must be ≥ 18 years of age when signing the informed consent form.
3. Patients must exhibit Eastern Cooperative Oncology Group (ECOG) performance status 0- 2 with no disease deterioration over the previous 2 weeks.
4. 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.).
5. 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.
6. SLL patient should have at least one measurable lesion (lymph node longest diameter > 1.5 cm or extranodal lesion longest diameter > 1.0 cm).
7. 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).
8. Patients should have the ability to comply with study requirements on study treatment and follow up.
9. 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.
10. 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 16

1. 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).
2. Richter transformation has been diagnosed or suspected at enrollment.
3. Lesions involving the central nervous system.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. History of ongoing drug-induced pneumonitis
10. History of confirmed progressive multifocal leukoencephalopathy (PML).
11. 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.
12. 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.
13. Patients with severe or poorly controlled systemic diseases as judged by the investigator or other evidence, including poorly controlled active bleeding.
14. Personnel involved in the planning and execution of the study (only applicable for staff of sponsor and study site).
15. Female patient who are breast feeding or pregnant.
16. The patient is unlikely to comply with study procedures, restrictions or requirements as judged by the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • Progression free survival (PFS) assessed by Independent Review Committee (IRC) per iwCLL 2018/Lugano 2014

Secondary endpoints 3

1. • PFS assessed by investigator • Objective response rate (ORR) and duration of response (DoR) assessed by IRC and investigator • Overall survival (OS) • Time to next treatment (TTNT) • EuroQol Group 5-level EQ-5D Questionnaire (EQ5D-5L) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
2. • Safety profiles, for example, adverse events (AEs), serious adverse events (SAEs), ≥ Grade 3 AEs, etc., per Common Terminology Criteria in Adverse Events v5.0 (CTCAE v5.0)
3. • Plasma concentration of DZD8586 and DZ4581, and derived corresponding PK parameters

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 16

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Sponsor organisation

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Address

No 199 Liangjing Road, Zhangjiang Hi Tech Park Pudong Zhangjiang Hi Tech Park Pudong

City

Shanghai

Postcode

201203

Country

China

Scientific contact point

Organisation

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Contact name

Frank Fang

Public contact point

Organisation

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Contact name

Frank Fang

Third parties 14

Locations

2 EU/EEA countries · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 30 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications