Waldenstrom Macroglobulinemia
Conditions
Brief summary
Phase Ib/II study of safety, tolerability, efficacy and PK of APG-2575 as a single agent or in combination with other therapeutic agents including ibrutinib or rituximab.
Detailed description
This is an open-label, multi-center Phase Ib/II study of safety, tolerability, efficacy and PK of APG-2575 as a single agent or in combination with other therapeutic agents including ibrutinib or rituximab. The study consists of the dose escalation and the dose expansion phases. The clinical trial will have multiple arms with ability to subsequently add more treatment arms based upon clinical activity of APG2575 in WM. Initially the study will contain 3 arms noted below, all the arms are independent. Arm A: APG-2575 will be administered as a single agent to determine the MTD/RP2D in subjects who are relapsed/resistant or intolerant to ibrutinib or other BTK inhibitors. The Dose escalation phase of APG-2575 as monotherapy will use mTPI-2 design. The starting target dose (using ramp-up if needed) is 400 mg (dose level; DL1) and will be increased to 600 mg (DL2), 800 mg (DL3) accordingly. Doses can be increased to higher level depending on safety and PK results based on discussions of the Investigators and Sponsor. APG-2575 will be administered orally once daily until time of progression or unacceptable toxicity. After the MTD/RP2D is determined, up to 12 additional patients will be enrolled at RP2D in dose-expansion phase to further evaluate safety and efficacy of APG-2575. Arm B: APG-2575 will be administered in combination with ibrutinib in subjects with previously untreated WM.
Interventions
DRUGAPG2575 400 mg
APG2575 400 mg
DRUGAPG2575 600 mg
APG2575 600 mg
DRUGAPG2575 800 mg
APG2575 800 mg
Sponsors
Ascentage Pharma Group Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
APG2575 400 mg ramp up arm
Eligibility
Sex/Gender
ALL
Age
18 Years to 95 Years
Healthy volunteers
No
Inclusion criteria
* Criteria for inclusion: Patients must meet all of the following inclusion criteria to be eligible for participation in this study: 1. Local confirmed clinicopathological diagnosis of WM in accordance with the consensus panel of the Second International Workshop on WM (Owen 2003). 2. WM patients with symptomatic and measurable disease (defined as presence of serum immunoglobulin M (IgM)\>0.5g/dL), requiring treatment as per mSMART guidelines (Kyle 2003): with B symptoms (fever, night sweats, fatigue, night sweats weight loss), progressive lymphadenopathy or splenomegaly, anemia (hemoglobin value of \<10 g/dL) or platelet count \<100\*109/L due to marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy due to WM, systemic amyloidosis related to WM, renal insufficiency related to WM, or symptomatic cryoglobulinemia may also be indications for therapy. 3. For Arm A only: Have received at least one prior therapy for WM. Patient must have either failed (defined as progressing while on or within 6 months of treatment with ibrutinib treatment) or intolerant to ibrutinib. 4. For Arm B only: Previously untreated WM. 5. For Arm C only: Have received at least one prior therapy, relapsed or refractory WM. 6. Adequate hematologic function defined as: 1. ANC ≥1.0 x 109/L independent of growth factor support within 7 days of the first dose with study drug. 2. Hemoglobin ≥9 g/dL without transfusion or growth factor support within 7 days of the first dose of study drug. 3. Platelet count ≥ 75 x 109/L without transfusion support within 7 days of the first dose of study drug. 7. Adequate hepatic and renal function defined as: 1. AST and ALT \< 2.5 x ULN (upper limit of normal) 2. Glomerular filtration rate (GFR) \>30mL/min 3. Bilirubin\< 1.5 x ULN 8. PT/INR ≤1.5 x ULN and PTT (aPTT) ≤1.5 x ULN. 9. ≥18 years of age. 10. Eastern Cooperative Oncology Group (ECOG) ≤1. 11. Life expectancy≥3 months. 12. Female subjects who are of non-reproductive potential (i.e., post-menopausal by history-no menses for ≥2 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry. 13. Male and female subjects who agree to use highly effective methods of birth control (e.g.,condoms, implants, injectables, combined oral contraceptives, some intrauterine devices\[IUDs\], sexual abstinence, or sterilized partner) during the period of therapy and for 30 days after the last dose of study drug and 90 days (males) after the last dose of study drug. Symptomatic disease meeting at least 1 of the recommendations from the Second International Workshop on Waldenström Macroglobulinemia for requiring treatment (Kyle 2003): 1. Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as one or more of the following disease-related symptoms or signs: 1. Unintentional weight loss ≥10% within the previous 6 months prior to Screening 2. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks prior to Screening without evidence of infection 3. Night sweats for more than 1 month prior to Screening without evidence of infection 2. Clinically relevant fatigue which is not relieved by rest due to WM 3. Symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises 4. Lymphadenopathy which is either symptomatic or bulky (≥5cm in maximum diameter) 5. Symptomatic hepatomegaly and/or splenomegaly and/or organ tissue infiltration 6. Peripheral neuropathy due to WM 7. Symptomatic cryoglobulinemia 8. Cold agglutinin anemia 9. IgM related immune hemolytic anemia and/or thrombocytopenia 10. Nephropathy related to WM 11. Amyloidosis related to WM 12. Hemoglobin ≤10g/dL 13. Platelet count \<100 x109/L 14. Serum monoclonal protein \>5g/dL, with or without overt clinical symptoms. 15. Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.
Exclusion criteria
* Criteria for exclusion: Patients who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Toxicity Endpoint: dose limiting toxicity (DLT) | 42 days | DLT will be defined based on the rate of drug-related grade 3-5 adverse events experienced within the first 6 weeks (2 cycles) of study treatment. These will be assessed via CTCAE version 5.0 |
| Maximally tolerated dose (MTD) | 42 days | MTD will be determined based on DLTs observed during the first 6 weeks (2 cycles) of study treatment |
Countries
Australia, China, United States
Outcome results
None listed