A Prospective, Single-Arm, Phase II Clinical Study Evaluating the Efficacy and Safety of Thiotepa in Combination With Pirtobrutinib (a BTK Inhibitor) and Sintilimab (a PD-1 Inhibitor) for Frail or Relapsed/Refractory Primary or Secondary Central Nervous System Lymphoma
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- Zhejiang Cancer Hospital
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- ORR
Overview
Brief Summary
This is a prospective, single-Arm, phase II clinical study evaluating the efficacy and safety of thiotepa in combination with pirtobrutinib (a BTK Inhibitor) and sintilimab (a PD-1 Inhibitor) for frail or relapsed/refractory primary or secondary central nervous system lymphoma.It includes screening phase， induction therapy phase, and maintenance therapy phase.The screening period is defined as within 14 days prior to the first dose.Induction Treatment Phase: Enrolled subjects will receive a combination regimen of thiotepa, pirtobrutinib, and sintilimab. Treatment is administered in 21-day cycles for up to 6 cycles. Patients who achieve a disease response may proceed to consolidation therapy with either autologous hematopoietic stem cell transplantation or whole-brain radiotherapy at the investigator's discretion.Maintenance Treatment Phase: For patients who do not receive consolidation therapy with autologous transplantation or whole-brain radiotherapy, maintenance treatment with pirtobrutinib plus sintilimab will be initiated (for up to 1 year). Patients who receive any consolidation therapy will not proceed to maintenance treatment.Treatment response will be assessed throughout the study using the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria. The trial will monitor patient survival data, objective response rate (ORR), and safety parameters.Upon discontinuation of study treatment or completion of the 1-year treatment period, subjects will enter the follow-up phase. During follow-up, radiographic assessments (contrast-enhanced CT of the involved site is recommended) will be performed according to the following schedule: every 3 months for the first 2 years, every 6 months from Year 3 to Year 5, and annually after 5 years, until the end of the follow-up period. For subjects who have not withdrawn consent, survival information (including date and cause of death, subsequent anti-tumor therapies, etc.) will be collected every 3 months via telephone and/or clinical visit.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histopathologically confirmed relapsed primary central nervous system lymphoma (PCNSL) of B-cell lineage, or secondary central nervous system lymphoma (SCNSL) with a previously confirmed B-cell origin primary lesion but without evidence of active extracranial systemic involvement.
- •The patients or their legal guardians provide voluntary written informed consent.
- •Age\>=18 years, both male and female.
- •Karnofsky Performance Status (KPS) score\>=
- •Patients deemed unsuitable for methotrexate (MTX)-based systemic chemotherapy ("unfit"), including but not limited to: patients assessed as unsuitable for chemotherapy or frail according to a simplified Geriatric Assessment (sGA) criteria; patients with contraindications to MTX (e.g., renal insufficiency, serous cavity effusions, oral mucositis, etc.); or patients who refuse high-dose methotrexate (HD-MTX) chemotherapy.
- •Life expectancy of greater than 3 months, as judged by the investigator.
- •Patients with parenchymal lesions (\>10\*10mm ) on contrast-enhanced cranial MRI or those with leptomeningeal disease only, require cytological examination of cerebrospinal fluid (CSF) to confirm the presence of lymphoma cells and/or imaging findings consistent with CSF results. These assessments must be completed within 14 days prior to enrollment.
- •If the patients have received prior anti-tumor therapy, all treatment-related non-hematologic toxicities must have recovered to Grade 1 or baseline (according to NCI CTCAE version 5.0, with the exception of alopecia).
- •Bone marrow and organ function must meet the following criteria (without transfusion, G-CSF support, or corrective therapy within 14 days prior to informed consent):
- •Hematological: Absolute neutrophil count (ANC) \>=1.5\*10\^9/L (1500/mm\^3), platelets \>=75\*10\^9/L, hemoglobin\>=8 g/dL (If bone marrow is involved, then platelets\>=50\*10\^9/L, ANC \>=1.0\*10\^9/L, and hemoglobin\>=7 g/dL are acceptable).
Exclusion Criteria
- •The patients with secondary central nervous system lymphoma (SCNSL) who have lesions outside the CNS and require systemic treatment.
- •Received chemotherapy, radiotherapy, immunotherapy or antibody-based treatments for anti-tumor purposes within 4 weeks prior to the first administration (or within 5 half-lives), those who had used small molecule targeted drugs or traditional Chinese medicine with anti-tumor indications within 2 weeks, and those who had received monoclonal antibody conjugate drug treatments within 10 weeks.
- •Receipt of any vaccine (including but not limited to vaccines for COVID-19, influenza, pneumonia, shingles, hepatitis B, etc.) within 4 weeks before taking the medicine for the first time.
- •Concurrent enrollment in another interventional clinical study, or less than 4 weeks between the last dose of prior clinical trial treatment and the first dose in this study.
- •Previous treatment with thiotepa, PD-1 inhibitors, or BTK inhibitors is not excluded by default but requires benefit-risk assessment by the investigator. Subjects with a history of Grade \>=3 immune-related adverse events (per NCI CTCAE v5.0) attributed to these agents are excluded.
- •History of active bleeding within 4 weeks before the first dose; need for therapeutic anticoagulation during the study (e.g., warfarin or vitamin K antagonists); or any condition associated with elevated bleeding risk or coagulopathy per investigator judgment (e.g., high-risk esophageal varices, active ulcer disease).
- •Treatment with moderate or strong CYP3A4/5 inhibitors or inducers is required within 2 weeks before the first administration or during the study period.
- •Concurrent presence of other malignant tumors requiring antineoplastic treatment.
- •Having uncontrolled or significant cardiovascular diseases, including (but not limited to):
- •Any of the following conditions occurring within 6 months before the first administration: congestive heart failure with New York Heart Association class \>= 3, myocardial infarction, unstable angina pectoris, arrhythmia requiring treatment at screening, or left ventricular ejection fraction (LVEF) \< 50%;
Arms & Interventions
Thiotepa, Pirtobrutinib , Sintilimab
Screening is defined as within 14 days before the first dose of study treatment. Induction Treatment Phase, enrolled subjects will receive a combination regimen consisting of thiotepa, pirtobrutinib, and sintilimab. This induction treatment will be given in 21-day cycles for a maximum of 6 cycles. Maintenance therapy with pirtobrutinib plus sintilimab (up to 1 year) will be administered only to patients who do not receive autologous transplantation or whole-brain radiotherapy as consolidation. Patients who receive any consolidation therapy will not receive maintenance treatment. Treatment response will be assessed throughout the study using the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria. The trial will monitor patient survival data, objective response rate (ORR), and safety parameters.Upon discontinuation of study treatment or completion of the 1-year treatment period, subjects will enter the follow-up phase.
Intervention: Thiotepa, Pirtobrutinib , Sintilimab(TPS) (Drug)
Outcomes
Primary Outcomes
ORR
Time Frame: 21 days after the end of treatment
Objective Response Rate
Secondary Outcomes
- CRR(21 days after the end of treatment)
- PRR(21 days after the end of treatment)
- PFS(the time from the date of initial treatment until the date of disease progression or death from any cause, whichever occurs first, assessed up to 24 months)
- OS(the time from the date of initial treatment until the date of death from any cause, assessed up to 24 months)
- AE(from the first day of treatment until 30 days after the last treatment)
- SAE(from the first day of treatment until 30 days after the last treatment)
Investigators
Yang haiyan
Chief Physician
Zhejiang Cancer Hospital