Phase I Study of Whole Brain Low Dose Radiotherapy Combined With ICI and Intrathecal Chemotherapy for Treatment of Refractory Meningeal Metastasis of Lung Cancer
Overview
- Phase
- Phase 1
- Intervention
- Whole Brain Low Dose Radiotherapy
- Conditions
- NSCLC
- Sponsor
- Sichuan University
- Enrollment
- 10
- Locations
- 1
- Primary Endpoint
- Incidence of treatment-related adverse events
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This phase I study aims to investigate the safety and efficacy of whole brain low dose radiotherapy (WB-LDRT) combined with ICI and intrathecal chemotherapy for treatment of refractory meningeal metastasis of lung cancer.
Detailed Description
This exploratory phase I study will be conducted in West China Hospital, Sichuan University. Three cohorts of whole brain low dose radiotherapy (3 patients per cohort) will be enrolled to determine the safety and efficacy of whole brain low dose radiotherapy combined with ICI and intrathecal chemotherapy for treatment of refractory meningeal metastasis of lung cancer. Subjects who fulfil all the inclusion criteria and none of the exclusion criteria will be enrolled and receive treatment with WB-LDRT at same dose (4 Gy/2f) with diffent cycles (decried as below), PD-1 inhibitor, pemetrexed chemotherapy, and intrathecal pemetrexed every 3 weeks (Q3w) for 4 cycles. Patients will receive WB-LDRT at 3 cohorts with increasing dose fractions: 4 Gy/2f of one cycle in group 1; 4 Gy/2f of two cycles in group 2; 4 Gy/2f of four cycles in group 3.
Investigators
You Lu
Chair of Department of Thoracic Cancer
Sichuan University
Eligibility Criteria
Inclusion Criteria
- •≥ 18 years old and ≤ 75 years old;
- •Patients with a definite diagnosis of leptomeningeal metastasis by cerebrospinal fluid cytology, or patients with clinical diagnosis combined with tumor history, neuroimaging, clinical manifestations, cerebrospinal fluid examination, etc.;
- •Patients with a clear history of lung carcinoma, including histopathological diagnosis or a combination of cytopathology and imaging, and failure of standard treatment;
- •Efficacy of extracranial lesions SD;
- •Patients with no contraindications to craniocranial radiotherapy were judged by radiotherapy doctors. Subjects who agree to receive immunotherapy, Lumbar puncture, intrathecal chemotherapy, and radiotherapy;
- •Expected survival ≥3 months, PS score ≤3;
- •Agree to provide cerebrospinal fluid, blood and tissue samples for biomarker testing;
- •The main organs function normally, no serious blood, heart, lung, liver, kidney, bone marrow and other functional abnormalities and immune deficiency diseases;
- •One week before enrollment, bone marrow and liver and kidney function met the following criteria:
- •① Hemoglobin ≥80 g/L, neutrophils ≥1.5×10\^9/L and platelets ≥70×10\^9/L;
Exclusion Criteria
- •Active autoimmune disease or history of autoimmune diseases;
- •Congenital or acquired immunodeficiency;
- •Uncontrolled cardiac clinical symptoms or diseases;
- •Severe infection or severe comorbidities, such as bleeding peptic ulcer, ileus, heart failure, renal failure, or poorly controlled diabetes;
- •History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation;
- •Other systemic malignancies within the last 5 years;
- •Allergy to any test drug;
- •Uncontrolled epilepsy, neurological failure, or severe treatment-related neurological impairment, uncontrollable psychosis, and other conditions deemed unsuitable for inclusion by the investigator;
- •Pregnant and lactating women, subjects with reproductive capacity are unwilling to take effective contraceptive measures.
Arms & Interventions
whole brain LDRT + ICI + intrathecal chemotherapy
The treatment regimen consisted of intrathecal chemotherapy (via lumbar puncture, pemetrexed 30 mg, once per three weeks, 4 cycles in total), PD-1 inhibitor (Sintilimab, via intravenous infusion, once per three weeks, 4 cycles in total)), pemetrexed chemotherapy (via intravenous infusion, once per three weeks, 4 cycles in total) and radiotherapy. Whole brain LDRT will be administered at 3 cohorts with increasing dose fractions: 4 Gy/2f of 2 fraction (administered a daily dose of 2 Gy for two days) in group 1; 4 Gy/2f of 4 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 2 cycles in total) in group 2; 4 Gy/2f of 8 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 4 cycles in total) in group 3.
Intervention: Whole Brain Low Dose Radiotherapy
whole brain LDRT + ICI + intrathecal chemotherapy
The treatment regimen consisted of intrathecal chemotherapy (via lumbar puncture, pemetrexed 30 mg, once per three weeks, 4 cycles in total), PD-1 inhibitor (Sintilimab, via intravenous infusion, once per three weeks, 4 cycles in total)), pemetrexed chemotherapy (via intravenous infusion, once per three weeks, 4 cycles in total) and radiotherapy. Whole brain LDRT will be administered at 3 cohorts with increasing dose fractions: 4 Gy/2f of 2 fraction (administered a daily dose of 2 Gy for two days) in group 1; 4 Gy/2f of 4 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 2 cycles in total) in group 2; 4 Gy/2f of 8 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 4 cycles in total) in group 3.
Intervention: Pemetrexed
whole brain LDRT + ICI + intrathecal chemotherapy
The treatment regimen consisted of intrathecal chemotherapy (via lumbar puncture, pemetrexed 30 mg, once per three weeks, 4 cycles in total), PD-1 inhibitor (Sintilimab, via intravenous infusion, once per three weeks, 4 cycles in total)), pemetrexed chemotherapy (via intravenous infusion, once per three weeks, 4 cycles in total) and radiotherapy. Whole brain LDRT will be administered at 3 cohorts with increasing dose fractions: 4 Gy/2f of 2 fraction (administered a daily dose of 2 Gy for two days) in group 1; 4 Gy/2f of 4 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 2 cycles in total) in group 2; 4 Gy/2f of 8 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 4 cycles in total) in group 3.
Intervention: Sintilimab
whole brain LDRT + ICI + intrathecal chemotherapy
The treatment regimen consisted of intrathecal chemotherapy (via lumbar puncture, pemetrexed 30 mg, once per three weeks, 4 cycles in total), PD-1 inhibitor (Sintilimab, via intravenous infusion, once per three weeks, 4 cycles in total)), pemetrexed chemotherapy (via intravenous infusion, once per three weeks, 4 cycles in total) and radiotherapy. Whole brain LDRT will be administered at 3 cohorts with increasing dose fractions: 4 Gy/2f of 2 fraction (administered a daily dose of 2 Gy for two days) in group 1; 4 Gy/2f of 4 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 2 cycles in total) in group 2; 4 Gy/2f of 8 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 4 cycles in total) in group 3.
Intervention: Chemotherapy
Outcomes
Primary Outcomes
Incidence of treatment-related adverse events
Time Frame: 48 months
The incidence of treatment-related adverse events were measured for determing tolerability and safety. Adverse events (AEs) are evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Events of grade 3-5 are defined as moderate and severe adverse events.
Clinical response rate
Time Frame: 48 months
The RANO proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.
Secondary Outcomes
- Neurological progression-free survival (NPFS)(48 months)
- Overall survival(48 months)