Ibrutinib With Methotrexate and Temozolomide for Patients With Newly Diagnosed Primary CNS Lymphoma
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT04514393|
Recruitment Status : Not yet recruiting
First Posted : August 14, 2020
Last Update Posted : August 14, 2020
|Condition or disease||Intervention/treatment||Phase|
|Primary Central Nervous System Lymphoma PCNSL Non Hodgkin Lymphoma||Drug: Methotrexate Drug: Ibrutinib Drug: Temozolomide||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||33 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Study of Combination Treatment of Methotrexate, Ibrutinib, and Temozolomide (MIT Regimen) in Patients With Newly Diagnosed Primary CNS Lymphoma|
|Estimated Study Start Date :||December 1, 2020|
|Estimated Primary Completion Date :||December 1, 2023|
|Estimated Study Completion Date :||June 1, 2024|
Experimental: 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.
Intravenous methotrexate at 3.5g/m2 (standard hydration/leucovorin support) will be given on day 1 of all cycles，for up to 4 cycles.
Other Name: MTX
Oral ibrutinib will be given at a dose of 560 mg daily and will be continued daily after completion of methotrexate and temozolomide.Ibrutinib is continued until disease progression, intolerable toxicity or death.
Other Name: Imbruvica
Oral temozolomide will be given at 150mg/m2 from day1 to day 5 every 4 of all cycles，for up to 4 cycles.
Other Name: TMZ
- 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)
- 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.
- Complete response (CR) rate [ Time Frame: up to 24 months ]The CR rate is defined as the proportion of patients who achieve complete remission(CR)/unconfirmed complete (CRu) based on the 2005 Response Criteria of the International Primary CNS Lymphoma Collaborative Group (IPCG).
- Duration of response（DOR） [ Time Frame: up to 24 months ]Duration of response is defined as the time from the date of first occurrence of CR or PR to the date of the first documented PD or death due to any cause.
- Progression‐free survival (PFS) [ Time Frame: 1 year and 2 years ]1 year and 2 years PFS rate.Disease progression was based on the 2005 Response Criteria of the International Primary CNS Lymphoma Collaborative Group (IPCG)
- overall survival (OS) [ Time Frame: 1 year and 2 years ]1-year and 2-year OS rates.
- Describe the tumor mutation profile by NGS [ Time Frame: up to 24 months ]DNA from tumor tissue and CSF will be sequencing by next generation sequencing (NGS).Identify the PNCSL-related variants and gene expression alterations by NGS.
- Relationship between prognostic and gene mutation in patients with PCNSL [ Time Frame: up to 24 months ]Will be correlated with treatment response, mutational analysis using next-generation sequencing, and characterization of aberrant gene expression in PCNSL samples
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04514393
|Contact: Huiqiang Huang, Professor||+86 020 firstname.lastname@example.org|
|Department of Hematology Nanfang Hospital, The Southern Medical University|
|Guandong, Guangdong, China, 510515|
|Contact: Ru Feng, M.D +86 13725119762 email@example.com|
|Department of Medical Oncology, Sun Yat-sen University Cancer Center|
|Guangzhou, Guangdong, China, 510060|
|Contact: Huiqiang Huang +86 020 87343350 firstname.lastname@example.org|
|Principal Investigator: Huiqiang Huang|
|Sub-Investigator: Xiaoxiao Wang|
|Guangdong 999 Brain Hospital|
|Guangzhou, Guangdong, China|
|Contact: Linbo Cai|
|Principal Investigator:||Huiqiang Huang, Professor||Sun Yat-sen University|