Summary

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

Objectives

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 (PI3Kd), 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.

Eligibility

1. 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 PI3Kd 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.

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