Trial to Evaluate the Safety and Pharmacokinetics of HMPL-689 in Patients With Lymphomas

A Phase 1, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of HMPL-689 in Patients With Relapsed or Refractory Lymphoma

An open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability and PK of HMPL-689 in patients with relapsed or refractory lymphomas

This is a Phase 1, open-label, multicenter study of HMPL-689 administered orally to patients with relapsed or refractory lymphoma.

HMPL-689 is a selective and potent small molecule inhibitor targeting the isoform phosphoinositide 3'-kinase delta (PI3Kδ), a key component in the B-cell receptor signaling pathway

This study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2).

Dose Escalation Stage (Stage 1):

This stage will end when any of the following criteria is met:

• The dose level 1 demonstrates an excessive toxicity, ie, 3 dose limiting toxicities (DLTs) are observed out of the first 3 patients at dose level 1.
• The maximum sample size is reached.
• The MTD and/or RP2D is confirmed.

Dose Expansion Stage (Stage 2):

To further characterize the safety and explore the preliminary anti-tumor activity of HMPL-689 at RP2D, patients with B cell lymphoma will be enrolled in the dose expansion stage.

Inclusion Criteria:

1. (ECOG) performance status of 0 or 1;

2. Histologically confirmed lymphoma (tumor types are restricted to CLL/SLL, FL (grade 1-3a), MCL, MZL, LPL/WM, PTCL or CBCL);

3. Patients with relapsed or refractory NHL for whom:

   • Standard of care treatment options no longer exist (Stage 1 only);
   • Standard of care treatment options no longer exist with the exception of PI3K-delta inhibitors (Stage 2 only);

4. Expected survival of more than 24 weeks.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Primary central nervous system (CNS) lymphoma;

2. Any of the following laboratory abnormalities Absolute neutrophil count; <1.0×10^9/L, Hemoglobin <80 g/L Platelets <50 ×10^9/L

3. Inadequate organ function, defined by the following:

   • Total bilirubin ≥1.5 times the upper limit of normal (× ULN);
   • AST or ALT > 2.5 × ULN;
   • Estimated creatinine clearance (CrCl) per Cockcroft-Gault;
   • Dose Escalation stage of trial (Stage 1) - CrCl < 40 mL/min;
   • Dose Expansion stage of trial (Stage 2) - CrCl <30 mL/min;

4. International normalized ratio (INR) > 1.5 × ULN, activated partial thromboplastin time (aPTT) > 1.5 × ULN;

5. Serum amylase or lipase > ULN at screening or known medical history of serum amylase or lipase > ULN;

6. Patients with presence of second primary malignant tumors within the last 2 years;

7. Clinically significant history of liver disease;

8. Prior treatment with any PI3Kδ inhibitors;

9. Any prior use of the following: cancer therapy within 3 weeks of study treatment, GCSF within 7 days of screening, steroid therapy or targeted anti-neoplastic intent within 7 days of treatment, any use of strong CYP3A4 inducers within 2 weeks prior to initiation of study treatment, prior autologous transplant within 6 months of study treatment, prior allogenic stem cell transplant within 6 months of study treatment;

10. Clinically significant active infection or interstitial lung diseases (including drug induced pneumonitis);

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

12. Adverse events from prior anti-neoplastic therapy that have not resolved to Grade less than or equal to 1, except for alopecia;

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

14. Congenital long QT syndrome or QTc >470 msec;

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

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

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

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

19. History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis);

20. Patients with ongoing chronic gastrointestinal diseases;

21. 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.