A Study of HMPL-689 in Patients With Lymphomas Failed of Standard of Care or no Standard of Care Existed

A Study of HMPL-689 in Patients With Lymphomas Failed of Standard of Care or no Standard of Care Existed

A Phase 1 Open-Label Study to Assess the Safety, Pharmacokinetics and Preliminary Efficacy of HMPL-689 in Patients With Lymphomas Failed of Standard of Care or No Standard of Care Existed

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.

This study consists of a dose escalation stage (Stage I) and a dose expansion stage (Stage II). Dose escalation will be performed according to a modified toxicity probability interval scheme-2 (mTPI-2). Expansion stage of the study enrolled 143 patients with B cell lymphoma, including CLL/SLL, FL, MZL, DLBCL, MCL and PTCL, Patients were treated with RP2D as starting dose.

Arm A: patients with MZL (subtype including nodal, extra-nodal and splenic) who received ≥ 1 previous line of systematic treatment and at least one line included CD20-directed regimen Arm B: patients with CLL/SLL who received ≥ 1 previous line of systematic treatment and at least one of which included purine-based regimen or CD20-directed regimen Arm C: patients with FL (grade 1, 2, and 3a) who received ≥ 2 previous line of systematic treatment and at least one line included CD20-directed regimen Arm D: patients with MCL who received ≥ 2 previous line of systematic treatment and at least one line included CD20-directed regimen Arm E: patients with DLBCL (including GCB and non-GCB, Richter' transformation) who received ≥ 2 previous line of systematic treatment and at least one line included CD20-directed regimen Arm F: patients with PTCL who received ≥ 2 previous line of systematic treatment

Two strengths of HMPL-689 capsules (2.5 mg and 10 mg) will be used for clinical studies. The drug products are capsules.

Through study completion, 1 year after the last patient has enrolled in the study or all patients have discontinued the study, whichever comes sooner

Complete response rate (CR rate) is defined as the proportion of patients who have a CR Other lymphomas: Lugano Response Criteria for Hodgkin and Non-Hodgkin's Lymphoma [the Revised Response Criteria for Malignant Lymphoma (Cheson 2014)

Through study completion, 1 year after the last patient has enrolled in the study or all patients have discontinued the study, whichever comes sooner

Time to response (TTR) is defined as the date from the first dose of study drug to the date of first CR or PR

Through study completion, 1 year after the last patient has enrolled in the study or all patients have discontinued the study, whichever comes sooner

Duration of response (DoR): defined as the time from when the first CR or PR was achieved until the earlier of the first documentation of definitive disease progression or death from any cause Other lymphomas: Lugano Response Criteria for Hodgkin and Non-Hodgkin's Lymphoma [the Revised Response Criteria for Malignant Lymphoma (Cheson 2014)

Through study completion, 1 year after the last patient has enrolled in the study or all patients have discontinued the study, whichever comes sooner

Through study completion, 1 year after the last patient has enrolled in the study or all patients have discontinued the study, whichever comes sooner

Progression-free survival (PFS) is defined as the time from the first dose to the first occurrence of progression or death from any cause, whichever occurs first

Through study completion, 1 year after the last patient has enrolled in the study or all patients have discontinued the study, whichever comes sooner

Inclusion Criteria: Signed Informed Consent Form (ICF) Ability to comply with the protocol Age ≥ 18 years old Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Histologically confirmed lymphoma 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 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 Expected survival of more than 24 weeks 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: Patients with CNS(Central nervous system) involvement Any of the following laboratory abnormalities: Absolute neutrophil count < 1.5×109/L Hemoglobin <90 g/L Platelets< 100 ×109/L 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 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 Serum amylase or lipase >ULN at screening 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 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) Prior treatment with any PI3K inhibitors and discontinued due to disease progression Any anti-cancer therapy, including chemotherapy, radiotherapy within 3 weeks prior to initiation of study treatment G-CSF/blood transfusion is prohibited 7 days before the screening hematology test 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 Any monoclonal antibody for anti-neoplastic intent within 6 weeks or 2 half-lives, whichever is the longer, prior to initiation of study treatment Prior use of any anti-cancer vaccine Prior administration of radioimmunotherapy within 3 months prior to initiation of study treatment 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) Prior autologous transplant within 6 months prior to initiation of study treatment 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 Clinically significant active infection (e.g., pneumonia) Major surgical procedure within 4 weeks prior to initiation of study treatment Treatment within a clinical study of an investigational agent or using an investigational device within 30 days prior to initiation of study treatment Adverse events from prior anti-cancer therapy that have not resolved to Grade 1, except for alopecia Pregnant (positive pregnancy test) or lactating women New York Heart Association (NYHA) Class II or greater congestive heart failure Congenital long QT syndrome or QTc > 450 msec Currently use medication known to cause QT prolongation or torsades de pointes History of myocardial infarction or unstable angina within 6 months prior to initiation of study treatment History of stroke or transient ischemic attack within 6 months prior to initiation of study treatment Inability to take oral medication, prior surgical procedures affecting absorption, or active peptic ulcer disease History of inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis) History of drug-induced pneumonitis 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