Recurrent or refractory primary or secondary central nervous system lymphoma
Conditions
Interventions
Experimental group (Phase ?a):HZ-A-018 capsule
Experimental group (Phase ?b):HZ-A-018 capsule combined with high dose methotrexate
Experimental group (Phase ?):HZ-A-018 capsule
Sponsors
Beijing TianTan Hospital,Captial Medical University
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: 1.Age =18 years old, gender unlimited. 2.The patient or legal guardian signs the informed consent voluntarily. 3.KPS score =60. 4.Life expectancy =3 months as assessed by the investigator. 5.Pathology confirmed diagnosis of primary CNS lymphoma (PCNSL) of B-cell origin, primary vitreoretinal lymphoma (PVRL), or secondary CNS lymphoma (SCNSL) of B-cell origin confirmed by in previous primary lesions. 6.Have substantial lesions with measurable lesions and brain enhanced MRI showing disease progression (>10*10mm); Only meningeal lesions require cytological examination of cerebrospinal fluid (CSF) to confirm lymphoma cells and/or imaging findings consistent with CSF examination. Only in patients with ocular lesions, there were lesions or indicators that could evaluate efficacy (abnormal vision or vitreous opacity or lymphoma lesions visible on OCT or elevated IL-10 or IL-10/IL-6>1 in intraocular fluid). The above tests should be completed within 14 days prior to enrollment. 7. Monotherapy group: Relapsed/refractory PCNSL or SCNSL must have received at least one systemic treatment with HD-MTX for CNS lesions, without limiting the number of relapses; Patients with recurrent/refractory PVRL must have received at least one systemic or intraocular therapy containing HD-MTX (intravitreal injection of MTX/ rituximab). 8.HD-MTX combination group: Relapsed/refractory PCNSL or SCNSL must have received at least one systemic treatment for CNS, with no limit on the number of relapses (if they have received systemic treatment with HD-MTX, they must have been evaluated as effective after treatment, and can be evaluated by investigators to use HD-MTX therapy again); For newly diagnosed PCNSL or SCNSL, the patient did not receive any systematic treatment for the CNS. 9. Any non-hematologic toxicity (except for alopecia) associated with prior therapy should have recovered to Grade 1 or resumed to normal according to NCI CTCAE V5.0. 10.Bone marrow and organ function meet the following criteria (no blood transfusion, use of G-CSF, or treatment with medications within 14 days before screening): a) Bone marrow function: HZ-A-018 monotherapy group (Phase Ia and II) : Neutrophil absolute value =0.75×10^9/L (=0.5×10^9/L for patients with bone marrow infiltration), platelets =50×10^9/L, hemoglobin =80g/L; HZ-A-018 and HD-TX combination group (Phase Ib):neutrophil absolute value =1.5×10^9/L, platelets =100×10^9/L, hemoglobin =80g/L; b) Liver function: serum total bilirubin =1.5×ULN (=3.0×ULN, if with liver metastases); aspartate transaminase (AST) and alanine transaminase (ALT) =2.5×ULN (=5.0×ULN, if with liver metastases); c) Coagulation function: International standardized ratio (INR) and activated partial thrombin time =1.5×ULN; d) Renal function: serum creatinine =1.5×ULN or estimated creatinine clearance =60mL/min (male: Cr (ml/min) = (140-age) × body weight (kg) /72× blood creatinine concentration (mg/dl); For female: Cr (ml/min) = (140- age) × body weight (kg) /85× blood creatinine concentration (mg/dl)). 11. Female subjects of childbearing age and male subjects of reproductive potential, who have no birth plan and agree to take at least two highly effective contraceptive measures throughout the study and up to 3 months after discontinuation of treatment: abstinence, physical contraception (e.g., sterilization, safety condom, etc.), hormonal contraceptive use started at least 3 months prior to the first dose of enrollment. Male subjects are prohibi
Exclusion criteria
Exclusion criteria: 1. Patients with SCNSL need systemic treatment for lesions outside CNS. 2. Anti-tumor therapy with chemotherapy, radiotherapy, immunotherapy or antibody drugs within 4 weeks before the first administration (note: nitrosourea is within 6 weeks), treatment with small molecule targeted drugs or Chinese herbal medicine with anti-tumor indications within 2 weeks, and treatment with monoclonal antibody-drug conjugate therapy within 10 weeks. 3. Participate in another clinical trial and received the investigational drug within 4 weeks prior to the first dose of the investigational drug. 4.Received vaccinations (including but not limited to COVID-19, influenza, pneumonia, shingles, hepatitis B, etc.) within 4 weeks prior to the first dose of the investigational drug. 5. Use >8mg of dexamethasone or its equivalent daily to control CNS disease, or use systemic adrenal corticosteroids continuously for 14 days prior to the dose to control non-CNS disease. 6. Have other tumors that require positive treatment. 7. Received BTK inhibitors previously(such as ibrutinib, Zebrutinib, and obrutinib) were not exclusion criteria, except for patients who relapsed after response with regular treatment. 8. Received PI3K inhibitors or Syk inhibitors previously. 9. Have active bleeding within 4 weeks prior to the first dose, or require anticoagulant therapy such as warfarin or vitamin K antagonist during the study, or have a bleeding tendency (e.g., esophageal varices at risk of bleeding, focal active ulcer lesions) or coagulation disorders in the opinion of the investigator. 10. Treatment with a moderate or strong CYP3A4/5 inhibitor or inducer within 2 weeks prior to initial administration or during the study period. 11. With uncontrolled or significant cardiovascular diseases, including but not limited to: a)Any of the following conditions within 6 months prior to the first dose: congestive cardiac failure (NYHA III or IV), myocardial infarction, unstable angina, or arrhythmia requiring treatment or left ventricular ejection fraction (LVEF) 470 msec(female)or >450 msec(male); d)Atrial fibrillation(EHRA score =2b); e)Uncontrolled hypertension, who are not suitable for the study in the opinion of the investigator. 12. Uncontrolled infections or which require intravenous antibiotic treatment. 13.Have active hepatitis B or C infection (hepatitis B: acute hepatitis B, chronic hepatitis B virus infection previously not treated, chronic hepatitis B carriers with HBV DNA = the limit of detection at the site; hepatitis C: positive for HCV RNA) or have syphilis. [Note: Inactive HBV surface antigen (HBsAg) carriers, patients with active HBV infection and receiving persistent anti-HBV suppression (with HBV DNA < the limit of detection at the site), and patients with cured HCV are acceptable for enrollment] 14. Infected with the human immunodeficiency virus (HIV). 15. Took a biopsy within 1 week or diagnostic surgery (but tests for diagnostic purposes are not considered surgical surgery) within 6 weeks prior to the first dose of investigational drug, except for the in
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety and tolerability(Phase?a);Determination of maximum tolerated dose (MTD) and phase II recommended dose (RP2D) ;Safety and tolerability(?b);Objective response rate(Phase ?); | — |
Secondary
| Measure | Time frame |
|---|---|
| Effectiveness evaluation;Pharmacokinetic evaluation; | — |
Countries
China
Contacts
Public ContactWenbin Li
Beijing TianTan Hospital,Captial Medical University
Outcome results
None listed