Título del ensayo: A Phase I, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of HMPL-523 in Patients with Relapsed or Refractory Lymphoma
Signed informed consent form (ICF).
Age ≥18 years.
ECOG performance status of 0 or 1.
Histologically confirmed lymphoma, including HL and NHL.
In the dose expansion stage, the tumor types may be restricted to any or all of the following tumor types. There may be approximately 10 patients in each cohort depending on response signals suggesting efficacy, except for 2 identified cohorts with approximately 20 patients per cohort: relapsed or refractory CLL/SLL, CLL/SLL post?BTK exposure (n=20), MCL, FL (Grade 1-3a) (n=20), MZL, WM/LPL, PTCL, CBCL, and/or HL.
Patients with relapsed or refractory lymphoma who have exhausted all approved therapy options as defined below:
- Refractory to any prior regimen, defined as no response (CR or PR) to previous therapies, or progression within 6 months of completion of the last dose of prior therapy.
- Those who can no longer tolerate/withstand cytotoxic chemotherapy and/or available standard of treatment/care. Where safety profile and risks of toxicity of other treatment options far outweigh any possible clinical benefit.
- Those with no curative standard of treatment or where available treatments are not reasonable or do not make sense. In particular, in the opinion of the attending primary investigator, those who will benefit from a new class of compound with a different mechanism of action.
In the dose expansion stage, patients must have measurable disease for an objective response assessment, except for patients with CLL and WM/LPL.
Patients with primary central nervous system lymphoma.
Any of the following laboratory abnormalities:
- Absolute neutrophil count 1.0×109/L
- Hemoglobin 80 g/L
- Platelets <50×109/L
Inadequate organ function, defined by the following:
- Total bilirubin 1.5 times the upper limit of normal ( ULN) with the following exception: o Patients with known Gilbert’s disease who have serum bilirubin level 3 ULN and normal AST and ALT may be enrolled.
- AST and/or ALT 2.5 ULN with the following exception:
o In the dose expansion stage, patients with documented disease infiltration of the liver may have AST and ALT levels 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
- Serum amylase or lipase >ULN
- International normalized ratio (INR)1.5 ULN or activated partial thromboplastin time (aPTT) 1.5 ULN.
- Patients with clinically detectable second primary malignant tumors at enrollment or other malignant tumors within the last 2 years (with the exception of radically treated basal cell or squamous cell carcinoma of the skin, in situ cervix, or in situ breast cancer)
- Any anticancer therapy, including chemotherapy, hormonal therapy, biologic therapy, vaccine, or radiotherapy, within 3 weeks prior to the initiation of study treatment.
- Herbal therapy within 1 week prior to the initiation of study treatment (3 weeks for St. John’s wort).
- Prior administration of radioimmunotherapy within 3 months before the initiation of study treatment.
- Use of strong cytochrome P450 enzyme (CYP)3A4 inhibitors or inducers and substrates of CYP3A4, CYP2B6, or CYP1A2, which are identified as narrow therapeutic drugs, within 14 days prior to the initiation of study treatment (refer to Appendix 7).
- Adverse events (AEs) from prior anticancer therapy that have not resolved to Grade ≤1, except for alopecia.
- Prior autologous stem cell transplant within 6 months prior to the initiation of study treatment.
- Prior allogeneic stem cell transplant within 6 months prior to the initiation of study treatment or with any evidence of active graft versus host disease or requirement for immunosuppressants within 28 days prior to the initiation of study treatment.
- Clinically significant active infection (eg, pneumonia) and interstitial lung diseases: see Appendix 14 for coronavirus disease 2019 (COVID-19) risk assessment and vaccine guidance.
- Major surgical procedure within 4 weeks prior to the initiation of study treatment.
- 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).
- Pregnant (positive serum beta human chorionic gonadotropin [β-HCG] or urine test) or lactating women.
- New York Heart Association Class II or greater congestive heart failure.
- Congenital long QT syndrome or corrected QT interval with Fridericia (QTcF) > 480 msec.
- Current use of medication known to cause QT prolongation or Torsades de Pointes (see full list at https://crediblemeds.org/).
- History of myocardial infarction or unstable angina within 6 months prior to the initiation of study treatment.
- History of stroke or transient ischemic attack within 6 months prior to the initiation of study treatment.
- Inability to take oral medication, prior surgical procedures affecting absorption, or active peptic ulcer disease.
- Treatment in a clinical study within 30 days prior to the initiation of study treatment.
- Ongoing psychiatric disorders, in particular, patients with depression and/or suicidal tendencies.
- Patients with pathological or organic fractures, in particular, those of unknown etiology.
- 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, may affect the interpretation of the results, or renders the patient at high risk from treatment complications.
This is a Phase I, open-label, multicenter study of HMPL-523 administered orally to patients with relapsed or refractory lymphoma who have exhausted approved therapy options. This study consists of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2).