| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and/or Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL). |
| Nawracająca i/lub oporna przewlekła białaczka limfocytowa (CLL) / Chłoniak z małych limfocytów (SLL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed and/or Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL). |
| Nawracająca i/lub oporna przewlekła białaczka limfocytowa (CLL) / Chłoniak z małych limfocytów (SLL) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009310 |
| E.1.2 | Term | CLL |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003910 |
| E.1.2 | Term | B-cell small lymphocytic lymphoma NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
Ib
Ocena bezpieczeństwa i tolerancji, identyfikacja działań toksycznych ograniczających dawkę (DLT) i określenie maksymalnej dawki tolerowanej (MTD)/dawki zalecanej dla fazy 2 (RP2D) produktu APG-2575, podawanego doustnie w monoterapii lub w połączeniu z rytuksymabem lub akalabrutynibem, u pacjentów z nawracającą i/lub oporną na leczenie CLL/SLL.
II
Ocena bezpieczeństwa i skuteczności produktu APG-2575 stosowanego w monoterapii lub w połączeniu z innymi produktami leczniczymi, takimi jak rytuksymab lub akalabrutynib, ibutrynib lub zanubrutinib u pacjentów z nawracającą i/lub oporną na leczenie lub wcześniej nieleczonym CLL/SLL. (Parametry oceny skuteczności będą obejmowały: ORR, CR, PR, PR-L, DOR, PFS, OS, MRD oceniane w ramach 8-kolorowej cytometrii przepływowej o minimalnej czułości wynoszącej 10–4 (0,01%) we krwi obwodowej i szpiku kostnym, czas do uzyskania CR i/lub ujemnego statusu MRD).
Dodatkowe cele badania- sekcja 4. Cele i punkty końcowe badania, str.40 |
|
| E.2.2 | Secondary objectives of the trial |
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. |
1. Określenie farmakokinetyki (PK) produktu APG-2575 podawanego w monoterapii lub w połączeniu z
a) rytuksymabem, b) akalabrutynibem c) ibrutinibem lub d) zanubrutinibem
2. Ocena zależności pomiędzy biomarkerami eksploracyjnymi
i biomarkerami prognostycznymi (w tym profilowania BH3) CLL/SLL a odpowiedzią na produkt APG-2575 podawanym w monoterapii i w kombinacji z rituximabem, acalabrutinibem, ibrutinibem lub zanubrutinibem.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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) <3 x ULN. Alkaline phosphatase < 3×ULN
7. 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.
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 willingness to sign a written informed consent form (the consent form must be signed by the patient prior to any study-specific procedures).
11. Willingness and ability to comply with study procedures and follow-up examination |
|
| E.4 | Principal 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 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.
18. Unstable angina or myocardial infarction within 3 months of enrollment
19. 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).
20. Unable to swallow capsules or have gastrointestinal conditions that could affect the absorption of APG-2575 in the opinion of the investigator.
21. 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.
22. Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoints include characterizing safety and tolerability, defining the MTD and recommended phase 2 dose (RP2D). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of study, since no interim analysis is planned according to the protocol |
|
| E.5.2 | 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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of study, since no interim analysis is planned according to the protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Ukraine |
| Australia |
| Russian Federation |
| United States |
| Hungary |
| Poland |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the date of the last protocol specified visit or assessment (including telephone contact) for the last patient or patient in the study. This date will be no later than 2 years after the last patient starts treatment or the date that the sponsor stops the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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