A Global Multicenter, Open Label, Randomized Phase 3 Registrational Study of Lisaftoclax (APG-2575) in Previously Treated Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (GLORA Study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ascentage Pharma Group Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

1 Aug 2024 → ongoing

Decision date (initial)

2024-09-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Ascentage Pharma Group Inc.

External identifiers

EU CT number

2023-508005-24-00

ClinicalTrials.gov

NCT06104566

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy, Others, Pharmacokinetic

To evaluate the progression-free survival (PFS) of lisaftoclax in combination with a BTKi compared with BTKi monotherapy in CLL/SLL patients previously treated with a BTKi, as determined by independent radiological review committee (IRC) using the iwCLL guidelines (Hallek M et al 2018).

Secondary objectives 6

1. Key Secondary Objective: To evaluate overall survival (OS) of lisaftoclax in combination with a BTKi versus BTKi monotherapy.
2. To determine efficacy of lisaftoclax plus a BTKi, compared with BTKi monotherapy by additional outcome measures including PFS by investigators, ORR rate, CR/CRi rate, DoR, uMRD rate.
3. To evaluate safety of lisaftoclax plus a BTKi, versus BTKi monotherapy.
4. To characterize the population pharmacokinetics of lisaftoclax.
5. To evaluate Patient-Reported Outcome (PRO) measures of lisaftoclax plus a BTKi versus BTKi monotherapy based on EORTC QLQ-C30.
6. To evaluate Health Economics Outcomes Research (HEOR) measures of lisaftoclax plus BTKi versus BTKi monoherapy based on Europol 5 Dimension (EQ-5D-5L) (Rabin and Charro 2001).

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Study design 2 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Aged ≥ 18 years.
2. Patients that have documented CLL/SLL who meet iwCLL 2018 criteria for CLL treatment guidelines are eligible. • Received a BTKi (acalabrutinib, ibrutinib, or zanubrutinib) monotherapy as 1st, 2nd, or 3rd line therapy for ≥ 12 months and have best response as either a or b: a. Stable disease b. PR with any of the following baseline risk factors: • Lymph node(s) diameter ≥ 2.5 cm, • ALC ≥ 25x 109 /L • Have ≥ 1 high-risk factor(s) (del17p/p53mut, unmutated IGHV, complex karyotype ≥ 5 factors (≥ 3 chromosomal abnormalities and ≥ 1 biological/structural aberrations).
3. ECOG performance status 0-2.
4. Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of randomization as follows: • Absolute neutrophil count ≥ 1.0 × 109/L • Platelet counts ≥ 75 × 109/L; in cases of thrombocytopenia • Total hemoglobin ≥ 9 g/dL -.
5. Adequate renal function • Creatinine clearance must be > 50 ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 – age) x actual bodyweight) / (72 x creatinine), for women x 0. 85) or an equally accurate method.
6. Adequate liver function as indicated by: • Total bilirubin ≤ 1.5 x ULN, except patients with known Gilbert’s Syndrome • Aspartate aminotransferase (AST) ≤ 2.5 x the institutional ULN value • Alanine aminotransferase (ALT) ≤ 2.5 x the institutional ULN value, • International Normalized Ratio (INR), Prothrombin Time (PT) or Activated Partial Thromboplastin time (APTT) ≤ 1.5 × ULN.
7. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.

Exclusion criteria 24

1. Achieved complete response (CR) or CRi status or disease progression while on BTKi (acalabrutinib, ibrutinib, zanubrutinib) monotherapy prior to study entry.
2. Transformation of CLL to Richter’s condition.
3. Prior treatment with venetoclax or other Bcl-2 inhibitors.
4. An individual organ/system impairment score of 4 as assessed by the cumulative illness rating scale (CIRS) definition limiting the ability to receive the study treatment, or any other life-threatening illness, medical condition, or organ system dysfunction that, in the investigator´s opinion, could compromise the patients’ safety or interfere with the absorption or metabolism of the study drugs (e.g., inability to swallow tablets or impaired resorption in the gastrointestinal tract).
5. Patients receiving acalabrutinib capsule-based therapy (not tablet) who require treatment with proton pump inhibitors (e.g, omeprazole esomeprazole, lansoprazole etc,) at study entry. (Patients receiving proton pump inhibitors who switch to H2 receptors antagonists or antacids are eligible for enrollment).
6. Patients who require or are receiving anticoagulation therapy with warfarin or equivalent vitamin K antagonists within 7 days of first dose of the study drug(s).
7. Patients who are pregnant or breastfeeding.
8. Has received the following within 7 days prior to the first dose of study drug: • Steroid therapy at a dose greater than prednisone 20 mg daily (or equivalent) for anti-neoplastic intent. • CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin or potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John’s wort.
9. Radiation within 14 days of study entry.
10. Continuance of toxicities due to prior radiotherapy or chemotherapy agents that have not recovered to ≤ grade 1 or baseline, except alopecia or neuropathy.
11. Failure to recover, as judged by the investigator, from prior surgical procedures. Patients with active wound healing, patients who have had major surgery within 28 days and minor surgery such as a biopsy within 14 days from first dose of study drug.
12. QTcF interval＞ 480ms 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).
13. Underlying clinically significant cardiovascular disease such as: symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening or any cardiovascular disability status of New York Heart Association Class ≥ 2.
14. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
15. Uncontrolled medical condition (e.g., diabetes).
16. Known to have central nervous system (CNS) involvement.
17. Prior malignancy within 2 years of treatment that required radiotherapy, or systemic therapy.
18. Patients treated with strong CYP3A4 inhibitors/inducers (patients can be washed out allowing 5 half-lives prior to study treatment and/or switched to non-prohibited drug.
19. History of stroke or intracranial hemorrhage within 3 months prior to registration for study screening or known bleeding disorders.
20. Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
21. Vaccination with live vaccines within 14 days prior to screening (30 days for patients in Czech Republic).
22. Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV, HCV infection or active COVID-19. (Patients who have received COVID-19 vaccination will be considered as eligible for the study.) (For patients from the Czech Republic, HBV, HCV and HIV testing is mandated at screening for these criteria to be met).
23. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly).
24. Fertile men or women of childbearing potential unless: surgically sterile or ≥ 2 years after the onset of menopause or willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 3 months after the end of study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS assessed by IRC defined as the time from randomization to the first occurrence of progression or relapse using the iwCLL guidelines (Hallek Metal 2018) or death from any cause, whichever occurs first.

Secondary endpoints 11

1. Key secondary endpoint: Overall survival (OS) defined as the time from randomization to the time of death from any cause.
2. Other secondary efficacy endpoints: PFS assessed by investigator is defined as the time from randomization to the first occurrence of progression or relapse using the iwCLL guidelines (Hallek Metal 2018) or death from any cause, whichever occurs first.
3. Other secondary efficacy endpoints: Overall response rate (ORR) is defined as the proportion of patients with complete response (CR), complete response with incomplete recovery (CRi) and partial repose (PR).
4. Other secondary efficacy endpoints: Proportion of patients with CR/CRi.
5. Other secondary efficacy endpoints: Duration of Response.
6. Other secondary efficacy endpoints: Proportion of patients with undetectable minimal residual disease.
7. Safety endpoints: Incidence and severity of adverse events, serious adverse events and changes in laboratory results, including hematology and biochemistry, during and within 30 days of treatment discontinuation.
8. Safety endpoints: Incidence of adverse events of interest, including atrial fibrillation and tumor lysis syndrome.
9. Pharmacokinetics endpoint: Population PK analysis.
10. Patient-Reported Outcome (PRO) Measures endpoint: The PRO outcome measures will evaluate the European Organization for Research and Treatment of Cancer (EORTC), Quality of Life Questionnaire Core-30 (QLQ-C30) and associated CLL module (QLQ-CLL17).
11. Health Economics and Outcomes Research (HEOR) endpoint: A EuroQoL5-Dimension (EQ-5D-5L) questionnaire will be used

Investigational products

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

Test 3

Comparator 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ascentage Pharma Group Inc.

Sponsor organisation

Ascentage Pharma Group Inc.

Address

700 King Farm Boulevard

City

Rockville

Postcode

20850-5736

Country

United States

Scientific contact point

Organisation

Ascentage Pharma Group Inc.

Contact name

Yifan Zhai, M.D., Ph.D.

Public contact point

Organisation

Ascentage Pharma Group Inc.

Contact name

Yifan Zhai, M.D., Ph.D.

Third parties 1

Locations

11 EU/EEA countries · 73 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 187 files

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

Application history

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