This is a Phase 1, open-label study of HMPL-689 administered orally to patients with lymphoma for whom failed of standard care or have no standard of care.This study consists of a dose escalation stage (Stage I) and a dose expansion stage (Stage II).

Both Stage I and Stage II include the following periods: screening period, treatment period, safety follow-up period, and extended progression free survival (PFS) follow-up period, as defined in Dose Escalation Stage (Stage I).

Dose escalation will be performed according to a modified toxicity probability interval scheme-2 (mTPI-2).To further characterize safety and efficacy of HMPL-689 at RP2D, expansion stage of the study enrolled 144 patients with B cell lymphoma, including CLL/ SLL, FL, MZL, DLBCL, MCL and PTCL. Patients were treated with RP2D as starting dose.

Inclusion Criteria:

1. Signed Informed Consent Form (ICF)
2. Ability to comply with the protocol
3. Age ≥ 18 years old
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Histologically confirmed lymphoma
6. Relapsed or refractory disease after failed of standard of care or no standard of care existed according to local guideline, and need further systematic treatment in the opinion of the investigator
7. At least 1 bi-dimensionally measurable nodal disease, defined as >1.5 cm (extra-nodal lesion>1.0 cm ) in its largest dimension by computerized tomography (CT) scan is required for patients with lymphoma other than CLL; lesions in anatomical locations (such as extremities or soft tissue lesions) that are not well visualized by CT may be measured by magnetic resonance image (MRI) instead
8. Expected survival of more than 24 weeks
9. Female patients of child-bearing potential and male patients with partners of child-bearing potential must agree to use double barrier contraception, condoms, sponge, foams, jellies, diaphragm or intrauterine device (IUD), contraceptives (oral or parenteral), Implanon®, injectable or other avoidance of pregnancy measures during the study and for 30 days after the last day of treatment. Post-menopausal females (>45 years old and without menses for >1 year) and surgically sterilized females are exempt from this criterion

Exclusion Criteria:

1. Patients with CNS(Central nervous system) involvement

2. Any of the following laboratory abnormalities:

   Absolute neutrophil count < 1.5×109/L Hemoglobin <90 g/L Platelets< 100 ×109/L

3. Inadequate organ function, defined by the following:

   Total bilirubin >1.5 x the upper limit of normal (ULN) with the following exception:

   • Patients with known Gilbert's disease who have serum total and direct bilirubin level ≤ 2.5 x the ULN and normal aspartate transaminase (AST) and alanine transaminase (ALT) may be enrolled

   AST or ALT >2.5 x the ULN with the following exception:

   • In the dose expansion stage:Patients with documented disease infiltration of the liver may have AST and ALT levels ≤ 5 x the ULN

   Serum creatinine >1.5 x the ULN or estimated creatinine clearance (Ccr) (i.e., estimated Glomerular Filtration Rate, [eGFR[ according to the method of Cockcroft-Gault )< 60 mL/min

4. International normalized ratio (INR) >1.5 x the ULN or activated partial thromboplastin time (aPTT) >1.5 x the ULN or Prothrombin Time (PT) >1.5 x the ULN

5. Serum amylase or lipase >ULN at screening

6. Patients with presence of second primary malignant tumors within the last 5 years, with the exception of the following non-invasive malignancies after curative treatment:

   Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for≥ 1 year prior to randomization

7. Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)

8. Prior treatment with any PI3K inhibitors and discontinued due to disease progression

9. Any anti-cancer therapy, including chemotherapy, radiotherapy within 3 weeks prior to initiation of study treatment

10. G-CSF/blood transfusion is prohibited 7 days before the screening hematology test

11. Any steroid therapy or approved targeted small molecule agents for anti-neoplastic intent within 7 days or approximately 5 half-lives, whichever is the longer, prior to initiation of study treatment

12. Any monoclonal antibody for anti-neoplastic intent within 6 weeks or 2 half-lives, whichever is the longer, prior to initiation of study treatment

13. Prior use of any anti-cancer vaccine

14. Prior administration of radioimmunotherapy within 3 months prior to initiation of study treatment

15. Prior use of any drug that is a strong inducer of CYP3A4, strong inhibitor of CYP3A4 within 2 weeks prior to initiation of study treatment (refer to Appendix 13)

16. Prior autologous transplant within 6 months prior to initiation of study treatment

17. Prior allogeneic stem cell transplant within 6 months prior to initiation of study treatment or with any evidence of active graft versus host disease or requirement for immunosuppressants within 21 days prior to initiation of study treatment

18. Clinically significant active infection (e.g., pneumonia)

19. Major surgical procedure within 4 weeks prior to initiation of study treatment

20. Treatment within a clinical study of an investigational agent or using an investigational device within 30 days prior to initiation of study treatment

21. Adverse events from prior anti-cancer therapy that have not resolved to Grade 1, except for alopecia

22. Pregnant (positive pregnancy test) or lactating women

23. New York Heart Association (NYHA) Class II or greater congestive heart failure

24. Congenital long QT syndrome or QTc > 450 msec

25. Currently use medication known to cause QT prolongation or torsades de pointes

26. History of myocardial infarction or unstable angina within 6 months prior to initiation of study treatment

27. History of stroke or transient ischemic attack within 6 months prior to initiation of study treatment

28. Inability to take oral medication, prior surgical procedures affecting absorption, or active peptic ulcer disease

29. History of inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis)

30. History of drug-induced pneumonitis

31. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications](streamdown:incomplete-link)