Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
APG-2575, rituximab, ibrutinib, chronic lymphocytic leukemia(CLL), small lymphocytic lymphoma(SLL)
Brief summary
The purpose of this study is to assess the safety, pharmacokinetic, pharmacodynamic and efficacy of APG-2575 single agent and in combination with other therapeutic agents in patients with relapsed/refractory CLL/SLL.
Detailed description
This is an open-label, multi-center Phase Ib/II study of safety, PK, PD and efficacy of APG-2575 as a single agent or in combination with rituximab or ibrutinib in relapsed/refractory CLL/SLL patients. This study consists of two parts: The first part is the APG-2575 single agent cohort expansion. The cohort expansion will be conducted at three dose levels of 400 mg, 600 mg, and 800 mg. And up to 15 patients are planned to be enrolled at each dose level. The second part contains two arms: APG-2575 combined with rituximab (Arm A) and APG-2575 combined with ibrutinib (Arm B). Both the two arms consist of two stages: dose escalation stage (first stage) and dose expansion stage (second stage). The first stage is the study of APG-2575 dose escalation combined with rituximab/ibrutinib. APG-2575 dose escalates according to the standard 3+3 design, the initial dose is 200mg, the dose of APG-2575 will be increased in subsequent levels, to 400mg, 600mg, 800mg respectively. The second stage is the MTD/RP2D expansion stage. Once the respective MTD/RP2D of arms A and B is determined, up to 15 subjects in each MTD/RP2D dose level would be enrolled. APG-2575 will be administered orally, once daily for consecutive 4 weeks as one cycle. Rituximab, on cycle 1 day 8(C1D8): 375mg/m2; on cycles 2-6 day l(C2-6D1): 500mg/m2, a total of six infusions. Ibrutinib 420 mg will be orally administered daily beginning from cycle 1 day 8 and continuously thereafter, every 4 weeks as a cycle.
Interventions
DRUGAPG-2575
APG-2575 orally once daily, every 28 days as a cycle.
DRUGRituximab
Rituximab 375mg/m2 ivgtt on C1D8 and 500mg/m2 ivgtt on C2-6D1.
DRUGIbrutinib
Ibrutinib 420mg orally once daily during C1D8-28 and following cycles.
Sponsors
Ascentage Pharma Group Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects who meet each of the following inclusion criteria are eligible to participate in this study: 1. Age ≥18 years old. 2. Diagnosis as relapsed/refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma according to the IWCLL NCI-WG guidelines revised in 2008. 3. Through radiological assessment, subjects with a lymph node length ≥ 10 cm require prior approval from the sponsor before enrollment. 4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 -1. 5. QTcF interval ≤450ms in males, and ≤470ms in females. 6. Adequate bone marrow function independent of growth factor and transfusion. 7. Adequate renal and liver function. 8. Willingness by males, female patients of child bearing potential, and their partners to use contraception by effective methods throughout the treatment period and for at least three months following the last dose of study drug. 9. Pregnancy test results of serum samples obtained within 14 days before the first study drug administration in fertile female subjects were negative; If the serum pregnancy test results obtained are\> 7 days from the first administration, urine sample obtained before the first study dose of study drug must be negative. 10. Male subjects must avoid sperm donation throughout the treatment period and for at least three months following the last dose of study drug. 11. Ability to understand and willingness to sign a written informed consent form approved by EC committee (the consent form must be signed by the patient prior to any screening or study-specific procedures). 12. Willingness and ability to comply with study procedures and follow-up examination.
Exclusion criteria
Patients who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities (DLT) of combination therapy | 28 days. | DLT will be graded according to NCI CTCAE Version 5.0. DLT will be defined as clinically significant drug-related adverse events during the cycle one. |
| Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose(RP2D) | 28 days. | MTD/RP2D will be determined based on DLTs observed during cycle one. |
| Adverse events of APG-2575 single agent | Up to 6 cycles (each cycle is 28 days). | Adverse events (AE) and serious adverse events (SAE) will be graded according to NCI CTCAE Version 5.0. |
| Objective Response Rate (ORR) of APG-2575 single agent | Up to 6 cycles (each cycle is 28 days). | ORR is defined by CR+ CRi + PR(according to NCI-WG CLL(2008)) and by CR+PR ( according to NHL Cheson (2007)).Response will be evaluated every 2 cycles (8 weeks) till complete 6 cycles treatment or one month after last dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum plasma concentration (Cmax) | 28 days. | Cmax of APG-2575 will be assessed in the patients in single agent or combo study. Cmax of ibrutinib will be assessed in the patients treated with APG-2575 combination with ibrutinib. |
| Area under the plasma concentration versus time curve (AUC) | 28 days. | AUC of APG-2575 will be assessed in the patients in single agent or combo study. AUC of ibrutinib will be assessed in the patients treated with APG-2575 combination with ibrutinib. |
| Objective Response Rate (ORR) of APG-2575 combination therapy | Up to 6 cycles (each cycle is 28 days). | ORR is defined by CR+ CRi + PR(according to NCI-WG CLL(2008)) and by CR+PR ( according to NHL Cheson (2007)).Response will be evaluated every 2 cycles (8 weeks) till complete 6 cycles treatment or one month after last dose. |
| Minimal residual lesions (MRD) of peripheral blood and/or bone marrow. | 2 years. | — |
| Survival benefit (PFS) of APG-2575 combination therapy | 2 years. | PFS,Time from the beginning of treatment to the first occurrence of Progressive Disease (PD) or death. |
Countries
China
Contacts
Primary ContactJianyong Li, M.D.
Outcome results
None listed