Relapsed and/or Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL). MedDRA version: 21.0 Level: LLT Classification code 10009310 Term: CLL System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: LLT Classification code 10003910 Term: B-cell small lymphocytic lymphoma NOS System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: APG-2575
Product Code: APG-2575
Pharmaceutical Form: Tablet
Sponsors
Ascentage Pharma Group Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. =18 years of age. 2. Histologically confirmed chronic lymphocytic leukemia or small lymphocytic leukemia (CLL/SLL) according to the 2018 international workshop (IW) CLL criteria who must have relapsed or be refractory to at least one prior therapy or naïve but could not tolerate traditional immunochemotherapy judged by investigator 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. 3. Eastern Cooperative Oncology Group (ECOG) score = 2. 4. 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. 5. 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/L independent of transfusion within 7 days of first dose of study drug. 6. 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) 7 days since obtaining the serum pregnancy test results. 8. 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. 9. Male patients must refrain from sperm donation, from initial study drug administration until 90 days after the last dose of study drug. 10. Ability to understand and willi
Exclusion criteria
Exclusion criteria: 1. Patient has undergone allogeneic stem cell transplant < 90 days. 2. Patient has active graft-versus-host disease or requires immunosuppressive therapy. 3. Patient has undergone CAR-T therapy < 30 days. 4. Active Richter’s Syndrome (patients with previously treated Richter’s Syndrome will be permitted if they are in remission) 5. Prior anti-Bcl-2 treatment (except patients who discontinued treatment for reasons other than disease progression and patients in the APG-2575 plus acalabrutinib cohortBTKi cohorts). 6. For the acalabrutinib BTKi and APG-2575 combination cohortcohorts: (1) Patients who discontinued due to acalabrutinib a specific BTKi toxicity may not be retreated with that BTKi (Note: Patients who received a BTK inhibitor BTKi therapy may participate whether, or not, they progressed following BTK inhibitorBTKi treatment). (2) Requires Patients in the cohort receiving acalabrutinib with the capsule formulation and not tablet formulation, who require concomitant treatment with a proton pump inhibitorsinhibitor (e.g,., omeprazole esomeprazole, lansoprazole, etc).) at study entry. (Patients receiving proton pump inhibitors who switch to H2 receptorsreceptor antagonists or antacids are eligible for enrollment tointo 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). 7. Active pathogen infections including human immunodeficiency virus syndrome (HIV) infection. 8. 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). 9. Has known central nervous system (CNS) involvement. 10. 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. 11. 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. 12. Patient is pregnant or breastfeeding. 13. 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 anti-neoplastic intent; b. CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin; c. Potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John’s wort; 14. Radiation within 14 days of study entry 15. Continuance of toxicities due to prior radiotherapy or chemotherapy agents that have not recovered to = grade 1 or baseline, except alopecia or neuropathy. 16. 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. 17. Has a cardiovascular disability status of New York He
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase Ib To assess the safety and tolerability, identify dose-limiting toxicities (DLT) and determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of APG-2575, administered orally as monotherapy or in combination with rituximab or acalabrutinib in patients with relapsed and/or refractory CLL/SLL. Phase II To assess the safety and efficacy of APG-2575 alone or in combination with other therapeutic agents such as rituximab or, acalabrutinib, ibrutinib or zanubrutinib in patients with relapsed and/or refractory or treatment naïve CLL/SLL. (Efficacy assessment parameters will include: ORR, CR, PR, PR-L, DOR, PFS, OS, MRD by 8-color flow cytometry with a minimum sensitivity of 10-4 (0.01%) in peripheral blood and bone marrow, time to CR and/or MRD negativity.) Amended Additional Objectives as per section 4 page 40 of the Protocol.;Secondary Objective: 1. 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. 2. 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 or, acalabrutinib, ibrutinib or zanubrutinib.;Primary end point(s): Primary endpoints include characterizing safety and tolerability, defining the MTD and recommended phase 2 dose (RP2D). ;Timepoint(s) of evaluation of this end point: End of study, since no interim analysis is planned according to the protocol | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 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. ;Timepoint(s) of evaluation of this end point: End of study, since no interim analysis is planned according to the protocol | — |
Countries
Australia, Hungary, Poland, Russian Federation, Ukraine, United States
Contacts
Public ContactYifan Zhai
Ascentage Pharma Group Inc.
Outcome results
None listed