MAPLE-1: This Phase I trial is trying to understand how safe, tolerable and effective different doses of a targeted therapy drug (APG-2575) is alone, or in combination with other treatments such as chemotherapy (including ibrutinib or rituzimab) in people with Waldenström MacroglobulinemiaA Phase Ib /II Open-label, Multi-center Study to Evaluate the Safety, Tolerability and Efficacy of APG-2575 Single Agent or in Combination With Ibrutinib or Rituximab in Patients With Waldenström Macroglobulinemia (MAPLE-1)

Inclusion

• 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.