Clinical trial NCT06454266: First-line Treatment of PCNSL With the Combination of Orelabrutinib, Rituximab, and Methotrexate (ORM Regimen)
Official title: Exploration of the Efficacy and Safety of Orelabrutinib Combined With Rituximab and Methotrexate (ORM Regimen) in the First-line Treatment of Primary Central Nervous System Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Central Nervous System Lymphoma
Lead sponsor: Ningbo No. 1 Hospital
Sponsor class: OTHER
First posted: 2024-06-12
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Exploring the efficacy and safety of first-line treatment of primary central nervous system lymphoma with the combination of orelabrutinib, rituximab and methotrexate (ORM regimen).

Detailed description: This is an open, single arm, single center clinical study. Untreated primary central nervous system lymphoma patients sign an informed consent form and meet all inclusion criteria. The subjects received treatment with the ORM regimen every 21 days for a total of 6 cycles.

The main purpose is to evaluate the anti-tumor activity (ORR) of the first-line treatment of primary central nervous system lymphoma with the combination of otinib, rituximab, and methotrexate (ORM regimen).

Secondary purpose:

1. Evaluate the safety and tolerability of first-line treatment of primary central nervous system lymphoma with the combination of otinib, rituximab, and methotrexate (ORM regimen).
2. Other efficacy evaluations of the first-line treatment of primary central nervous system lymphoma with the combination of otinib, rituximab, and methotrexate (ORM regimen) include CR, DOR, DCR, and PFS.
3. Evaluate the peripheral blood and cerebrospinal fluid pharmacokinetic characteristics of obrutinib and methotrexate.

The exploratory purpose is to investigate the relationship between the dynamic changes of cerebrospinal fluid ctDNA before and after treatment and the efficacy and prognosis.

Eligibility criteria: Inclusion Criteria:

1. Clinical diagnosis of primary central nervous system lymphoma (PCNSL) of B cell origin，confirmed by pathology (histology or cytology).
2. The patient voluntarily signs the informed consent form.
3. ECOG≤3 points.
4. According to the judgment of the researcher, the expected survival period is more than 3 months.
5. Have measurable lesions, and brain contrast-enhanced MRI shows solid lesions (\>10\*10mm) ; for those with only meningeal lesions, cytological examination of cerebrospinal fluid (CSF) is required to confirm lymphoma cells and/or imaging findings and CSF examination was consistent.
6. No previous systemic treatment for lymphoma, except corticosteroids;
7. Bone marrow and organ function meet the following standards (no blood transfusion, no use of G-CSF, no use of drug correction within 14 days before screening):

   ① Bone marrow function: Absolute value of neutrophils ≥1.5×109/L, platelets
   * 80×109/L, hemoglobin ≥80g/L;

     * Liver function: serum total bilirubin ≤1.5×ULN (≤3.0×ULN, if there is liver metastasis ); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5.0 × ULN, if there is liver metastasis); ③ Coagulation function: International normalized ratio (INR) and activated partial thrombin time ≤ 1.5 × ULN ;

       * Renal function: Serum creatinine ≤ 1.5 × ULN or estimated creatinine clearance ≥ 60 mL/min (male: Cr (ml/min) = (140-age) × weight (kg) / 72 × serum creatinine concentration (mg/dl) ); Female: Cr (ml/min) = (140-age) × weight (kg)/85 × serum creatinine concentration (mg/dl)).
8. Female subjects of childbearing age and male subjects with childbearing potential who have no childbearing plans with their partners during the study and within 3 months after discontinuing treatment must take one of the following measures during the entire study and within 3 months of discontinuing treatment. Effective contraception: abstinence, physical contraception (such as ligation, condoms, etc.), and the use of hormonal contraceptives should be started at least 3 months before the first dose of medication. Male subjects are prohibited from donating sperm within 3 months from the start of treatment to the end of treatment. The patient or legal guardian voluntarily signed the informed consent form.
9. Good compliance and willingness to comply with visit schedule, dosing plan, laboratory examinations and other test steps.

Exclusion Criteria:

1. The pathological diagnosis was T-cell lymphoma;
2. Have other tumors that require treatment;
3. Uncontrollable active infection;
4. Have uncontrollable or important cardiovascular diseases, including (but not limited to):

   * Any of the following occurring within 6 months before the first dose Conditions: congestive heart failure (NYHA class III or IV), myocardial infarction, unstable angina, or arrhythmia requiring treatment at screening, left ventricular ejection fraction (LVEF) \<50%;

     * Primary cardiomyopathy (such as dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, indeterminate cardiomyopathy); ③ History of clinically significant QTc phase prolongation, II degree type II atrioventricular conduction resistance lag or III degree atrioventricular block or QTc interval (F method) \>470msec (female) or \>480msec (male); ④ Atrial fibrillation (EHRA grade ≥ 2b); ⑤ Uncontrollable hypertension, as determined by the researcher were judged not to be suitable to participate in this study.
5. Suffering from active hepatitis B or C infection (hepatitis B: acute hepatitis B, untreated chronic hepatitis B virus infection, chronic hepatitis B carriers with HBV-DNA ≥ the detection limit of each center; hepatitis C: HCVRNA positive) or syphilis . Note: Inactive HBV surface antigen (HBsAg) carriers, subjects with active HBV infection and long-lasting anti-HBV suppression (HBV DNA \<detection limit of each center), and subjects who have been cured of HCV can be enrolled.
6. HIV-infected patients;
7. Have ever received an organ transplant or allogeneic stem cell transplant.
8. For female subjects, currently in pregnancy or lactation.
9. Those who have previously or currently have pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, etc., and are judged by the researcher to be unsuitable to participate.
10. There have been autoimmune diseases requiring systemic treatment (i.e., disease-modifying antirheumatic drugs, hormones or immunosuppressants) in the past 2 years, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, etc. Rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome-associated vascular thrombosis, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis. The following situations are allowed: autoimmune hypothyroidism or type I diabetes under stable treatment, hormone replacement therapy (such as thyroxine, insulin, or physiological hormone supplementation due to adrenal or pituitary insufficiency) is not considered systemic therapy and is allowed Join the group.

Primary outcomes:
measure: Overall response rate
timeFrame: up to 8 months
Secondary outcomes:
measure: Progress free survival time
timeFrame: up to36 months
measure: Overall survival
timeFrame: up to36 months
measure: Adverse events profile
timeFrame: up to 8 months
measure: MRD defined by cerebrospinal fluid ctDNA
timeFrame: up to 8 months
Other outcomes:
Locations:
city: Ningbo
country: China
facility: The First Affiliated Hospital of Ningbo University
state: Zhejiang
Study officials:
affiliation: First Affiliated Hospital of Ningbo University
name: Shaoying Chen
role: PRINCIPAL_INVESTIGATOR
References: