LISAFTOCLAX for Chronic lymphocytic leukemia | Small lymphocytic lymphoma

Inclusion criteria

• {"criterion_text":"- ≥18 years of age.\n- Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the patient prior to any study-specific procedures).\n- Willingness and ability to comply with study procedures and follow-up examination.\n- Histologically confirmed chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) according to the 2018 international workshop (IW) CLL criteria who must have relapsed or be refractory to at least one prior therapy for CLL/SLL and require treatment by 2018 IWCLL criteria. In addition, for APG-2575, 600 plus acalabrutinib combination may be (1) treatment naïve or (2) refractory to venetoclax. Patients in APG-2575 plus ibrutinib Cohort C and in APG-2575 plus zanubrutinib Cohort D may be relapsed/refractory or treatment naïve.\n- Eastern Cooperative Oncology Group (ECOG) score ≤ 2.\n- Patients must have objectively documented evidence of disease progression prior to study entry such as: escalating lymphocytes count with an increase > 50% over a period of two months or doubling time in less than 6 months; enlarging adenopathy or splenomegaly; increasing cytopenias; clinical B symptoms night sweats, fatigue, > 10 % weight loss in 6 months, fevers > 100.50 F or 38.00 C for ≥ one month without infection.\n- Adequate bone marrow function independent of growth factor: • Absolute neutrophil count (ANC)≥ 1.0× 109/L. • Platelet count ≥ 50 x 109/L (entry platelet count must be independent of transfusion within 7 days of first dose of study drug). • Hemoglobin ≥ 8.0 g/dL independent of transfusion within 7 days of first dose of study drug.\n- Adequate renal and hepatic function as indicated by: a. Creatinine clearance must be ≥ 50 mL/min, calculated using the Cockcroft and Gault formula(140-Age) x mas (kg)/ (72x creatinine mg/dL); multiply by 0.85 if female (Cockcroft 1976) or measured by 24-hour urine collection. b. Total bilirubin ≤1.5 x ULN, except patient with known Gilbert’s syndrome or resolving hemolytic anemia. c. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <3 x ULN. Alkaline phosphatase < 3×ULN\n- Females of childbearing potential (i.e. not postmenopausal for at least 2 years or surgically sterile) must have negative results for pregnancy test performed: a. At screening on a serum sample obtained within 14 days prior to the first study drug administration. b. Prior to dosing on a urine sample obtained on the first day of study drug administration, if it has been＞7 days since obtaining the serum pregnancy test results.\n- Females of childbearing potential and non-sterile males must practice at least one of the following methods of birth control with partner(s) throughout the study and for 90 days after discontinuing study drug: a. Total abstinence from sexual intercourse as the preferred lifestyle of the patient; periodic abstinence is not acceptable; b. Surgically sterile partner(s); acceptable sterility surgeries are vasectomy, bilateral tubal ligation, bilateral oophorectomy or hysterectomy; c. Intrauterine device (IUD); d. Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal jellies or cream AND a condom); e. Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for at least 3 months prior to study drug administration. If hormonal contraceptives are used, the specific contraceptive must have been used for at least 3 months prior to study drug administration.\n- Male patients must refrain from sperm donation, from initial study drug administration until 90 days after the last dose of study drug."}

Exclusion criteria

• {"criterion_text":"- Patient has undergone allogeneic stem cell transplant < 90 days.\n- Prior malignancy that requires treatment, with exception of hormonal therapy and any cancer with recurrence within 2 years of screening (except for non-melanoma skin cancer or adequately treated carcinoma in situ of cervix or breast). Cancer treated within 2 years with curative intent and without recurrence as well as prostate cancer on active surveillance are allowed.\n- Concurrent treatment with an investigational agent, received biologics (≤14 days), or small molecule targeted therapies (≤5 half-life) or other anti-cancer therapies (including chemotherapy) ≤14 days of first dose of study drug.\n- Patient is pregnant or breastfeeding.\n- Has received the following within 7 days prior to the first dose of study drug: a. Steroid therapy at a dose greater than prednisone 20 mg daily (or equivalent) for antineoplastic intent; b. CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin; c. Potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John’s wort;\n- Radiation within 14 days of study entry.\n- Continuance of toxicities due to prior radiotherapy or chemotherapy agents that have not recovered to ≤ grade 1 or baseline, except alopecia or neuropathy.\n- Failure to recover adequately, as judged by the investigator, from prior surgical procedures. Patients with active wound healing, patients who have had major surgery within 28 days from 1st dose of study drug.\n- Has a cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea or anginal pain.\n- Unstable angina or myocardial infarction within 3 months of enrollment.\n- QTcF interval＞ 480ms (Bazetts or Fredericia) 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).\n- Patient has active graft-versus-host disease or requires immunosuppressive therapy.\n- Unable to swallow capsules or have gastrointestinal conditions that could affect the absorption of APG-2575 in the opinion of the investigator.\n- Uncontrolled concurrent illness including, but not limited to: uncontrolled diabetes mellitus, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with the study requirements.\n- Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.\n- Patient has undergone CAR-T therapy < 30 days.\n- Active Richter’s Syndrome (patients with previously treated Richter’s Syndrome will be permitted if they are in remission).\n- Prior anti-Bcl-2 treatment (except patients who discontinued treatment for reasons other than disease progression and patients in the APG-2575 plus BTKi cohorts).\n- For the BTKi and APG-2575 combination cohorts: (1) Patients who discontinued due to a specific BTKi toxicity may not be retreated with that BTKi (Note: Patients who received a BTKi therapy may participate whether or not they progressed following BTKi treatment). (2) Patients in the cohort receiving acalabrutinib with the capsule formulation and not tablet formulation, who require concomitant treatment with a proton pump inhibitor (e.g., omeprazole esomeprazole, lansoprazole, etc.) at study entry. (Patients receiving proton pump inhibitors who switch to H2 receptor antagonists or antacids are eligible for enrollment into this study arm.) (3) Requires or is receiving anticoagulation therapy with warfarin or equivalent vitamin K antagonists within 7 days of first dose of the study drug(s).\n- Active pathogen infections including human immunodeficiency virus syndrome (HIV) infection.\n- Active hepatitis B infection, as defined seropositivity for Hep B surface antigen (HBsAg) or known active Hepatitis C infection as determined by Hepatitis C antibody with elevated liver enzymes as defined in the inclusion criteria or any other evidence of active Hepatitis C such as currently on treatment; or active COVID-19 infection. (Patients who have received COVID-19 vaccination will be considered as eligible for the study).\n- Has known central nervous system (CNS) involvement."}

Primary endpoints

• {"endpoint_text":"- Primary endpoints include characterizing safety and tolerability, defining the MTD and recommended phase 2 dose (RP2D).","definition_or_measurement_approach":"Assess safety and tolerability, identify dose-limiting toxicities (DLT) and determine maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) as described in Phase Ib objectives."}

Secondary endpoints

• {"endpoint_text":"- Secondary endpoints include determining the effectiveness of APG-2575 as monotherapy and in combination with other anticancer agents in patients with relapsed and/or refractory CLL by determining ORR (CR and PR) and MRD negativity.","definition_or_measurement_approach":"Effectiveness measured by ORR (CR and PR) and MRD negativity; MRD assessed by 8-color flow cytometry with minimum sensitivity of 10^-4 (0.01%) in peripheral blood and bone marrow; other efficacy measures include DOR, PFS, OS as described in Phase II objectives."}

Other endpoints

• {"endpoint_text":"- A- Determine the pharmacokinetics (PK) of APG-2575 when administered as: a single agent or in combination with, a) rituximab, b) acalabrutinib, c) ibrutinib, or d) zanubrutinib.\n- B- To evaluate the relationship between exploratory and prognostic biomarkers (including BH3 profiling) for CLL/SLL and response to APG-2575 when administered as a single agent and in combinations with rituximab, acalabrutinib, ibrutinib or zanubrutinib.","definition_or_measurement_approach":"PK will be determined for APG-2575 as monotherapy and in combination regimens. Biomarker analyses include exploratory and prognostic markers (including BH3 profiling) correlated with response; details per protocol's secondary objectives."}

Hungary

Earliest CTIS Part Ii Submission Date

12-09-2024

Latest Decision Or Authorization Date

16-04-2026

Processing Time Days

581

Number Of Sites

3

Number Of Participants

20

Poland

Earliest CTIS Part Ii Submission Date

12-09-2024

Latest Decision Or Authorization Date

15-04-2026

Processing Time Days

580

Number Of Sites

2

Number Of Participants

40

Primary sponsor

Full Name

Ascentage Pharma Group Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Everest Clinical Research Corporation

Responsibilities

codes: 10, 3, 6

Name

Parexel International (IRL) Limited

Responsibilities

code: 8

Third parties

• {"country":"Ireland","full_name":"Cromos Pharma Ireland Limited","duties_or_roles":"codes: 1, 12, 2","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"Everest Clinical Research Corporation","duties_or_roles":"codes: 10, 3, 6","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eurofins Central Laboratory LLC","duties_or_roles":"Laboratory Kits and Sample Storage","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Almac Clinical Services LLC","duties_or_roles":"Drug Depot","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"code: 8","organisation_type":"Pharmaceutical company"}