Phase II Study of Combination Treatment of Methotrexate, Ibrutinib, and Temozolomide (MIT Regimen) in Patients With Newly Diagnosed Primary CNS Lymphoma
Overview
- Phase
- Phase 2
- Intervention
- Methotrexate
- Conditions
- Primary Central Nervous System Lymphoma
- Sponsor
- Huiqiang Huang
- Enrollment
- 33
- Locations
- 3
- Primary Endpoint
- the toxicity profile of the ibrutinib/MTX/ temozolomide combination therapy
- Last Updated
- 4 years ago
Overview
Brief Summary
The purpose of the study is to test the efficacy and tolerability of a combination treatment of methotrexate, ibrutinib, and temozolomide (MIT regimen) in treating patients who have newly-diagnosed primary CNS lymphoma.
Detailed Description
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal Non-Hodgkin Lymphoma. Induction treatment of PCNSL in most reported single-arm or randomized trials includes high-dose methotrexate (HD-MTX)-based therapy, temozolomide, with or without cytarabine and the anti-CD20 antibody rituximab. A better combination remains undefined. Treatment is associated with considerable morbidity and disease recurrences with a 5-year survival of approximately 40%. The BTK inhibitor ibrutinib has shown antitumor activity in patients with recurrent or refractory PCNSL. However, tumor responses to single-agent ibrutinib in CNS lymphoma are often incomplete or transient. Efficacy and safety of ibrutinib in combination with cytotoxic agents are worth to be discovered. Grommes et al.have shown ibrutinib in combination with methotrexate and rituximab are safe and shows promising activity in recurrent/refractory CNS lymphoma. In comparison to their prior study with single-agent ibrutinib, the radiographic response of r/r PCNSL was higher with the ibrutinib/HD-MTX/rituximab combination regimen and PFS was longer with the combination therapy. The study has shown that ibrutinib combined with chemotherapy were superior to ibrutinib single agent and overcome the transient effect of ibrutinib in relapsed PCNSL. However, there are some limitations in interpreting Grommes' study results, especially the heterogeneous patient population with inclusion of both PCNSL and SCNSL. Most recently, the role of rituximab in PCNSL has become clearly. In the HOVON 105/ALLG NHL 24 study, the addition of rituximab to a methotrexate-based regimen did not demonstrate a significant benefit on clinical outcome. We therefore initiate this study aim to evaluate the activity and safety of ibrutinib in combination with Methotrexate and temozolomide (MIT regimen) in newly diagnosed PCNSL patients.
Investigators
Huiqiang Huang
professor
Sun Yat-sen University
Eligibility Criteria
Inclusion Criteria
- •Men and woman who are 18 to 70 years of age on the day of consenting to the study.
- •Histologically documented PCNSL
- •ECOG performance status ≤
- •Life expectancy of \> 3 months (in the opinion of the investigator).
- •Adequate bone marrow and organ function shown by:
- •Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
- •Platelets ≥ 75 x 10\^9/L and no platelet transfusion within the past 14 days prior to study registration
- •Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days prior to study registration
- •International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal
Exclusion Criteria
- •Patients eligible for this study must NOT MEET ANY of the following criteria:
- •Active concurrent malignancy requiring active therapy
- •Excluded medical conditions:
- •Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (New York Heart Association \> Class 2), unstable angina, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
- •Uncontrolled hypertension despite optimal medical management (per investigators assessment)
- •Patient has poorly controlled diabetes mellitus with a glycosylated hemoglobin \>8% or poorly controlled steroid-induced diabetes mellitus with a glycosylated hemoglobin of \>8%
- •Patient is known to have an uncontrolled active systemic infection (\>CTCAE grade 2) and recent infection requiring intravenous anti-infective treatment that was completed ≤14 days before the first dose of study drug
- •Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment
- •Non-healing wound, ulcer or bone fracture
- •Known bleeding diathesis (eg, von Willebrands disease) or hemophilia
Arms & Interventions
methotrexate, ibrutinib, and temozolomide (MIT regimen)
Methotrexate will be given on day 1 of each 28-day cycle；Ibrutinib will be given day 1-28 of each 28-day cycle; Temozolomide will be given day 1-5 of each 28-day cycle. Methotrexate and Temozolomide are given for up to 4 cycles; Ibrutinib is continued until disease progression, intolerable toxicity, or death.
Intervention: Methotrexate
methotrexate, ibrutinib, and temozolomide (MIT regimen)
Methotrexate will be given on day 1 of each 28-day cycle；Ibrutinib will be given day 1-28 of each 28-day cycle; Temozolomide will be given day 1-5 of each 28-day cycle. Methotrexate and Temozolomide are given for up to 4 cycles; Ibrutinib is continued until disease progression, intolerable toxicity, or death.
Intervention: Ibrutinib
methotrexate, ibrutinib, and temozolomide (MIT regimen)
Methotrexate will be given on day 1 of each 28-day cycle；Ibrutinib will be given day 1-28 of each 28-day cycle; Temozolomide will be given day 1-5 of each 28-day cycle. Methotrexate and Temozolomide are given for up to 4 cycles; Ibrutinib is continued until disease progression, intolerable toxicity, or death.
Intervention: Temozolomide
Outcomes
Primary Outcomes
the toxicity profile of the ibrutinib/MTX/ temozolomide combination therapy
Time Frame: up to 24 months
All subjects who received at least one dose of MIT will be included in the safety analysis. Adverse events will be graded by the investigator according to the NCI-CTCAE Version 5.0. Treatment-emergent adverse events (TEAEs) will be summarised and tabulated according to the primary system organ class and preferred term. Type, incidence, severity, and seriousness of adverse events (AEs) including physical examination, safety laboratory parameters, vital signs, and so on will be analyzed.
the overall response (complete response + partial response)，Investigator-Assessed
Time Frame: up to 24 months
The overall response rate (ORR) including complete response (CR), unconfirmed complete (CRu) and partial response (PR) according to the 2005 Response Criteria of the International Primary CNS Lymphoma Collaborative Group (IPCG)
Secondary Outcomes
- Complete response (CR) rate(up to 24 months)
- Duration of response（DOR）(up to 24 months)
- Progression-free survival (PFS)(1 year and 2 years)
- overall survival (OS)(1 year and 2 years)