Primary Central Nervous System LymphomaPhase 2NCT04514393
Ibrutinib With Methotrexate and Temozolomide for Patients With Newly Diagnosed Primary CNS Lymphoma
A Phase 2 study testing Methotrexate, Ibrutinib and Temozolomide in people with Primary Central Nervous System Lymphoma and PCNSL, run by Huiqiang Huang at 3 sites in China.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Primary Central Nervous System Lymphoma, PCNSL, Non Hodgkin Lymphoma
- What is being tested?
- Methotrexate, Ibrutinib and Temozolomide
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 33 participants
- Where
- 3 sitesChina
- Study dates
- 10 Oct 2020to 1 Jun 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 ≤ 2.
- 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
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- 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
- Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome
- Serum creatinine ≤ 2 times the upper limit of normal
- Lipase ≤ 1.5 x upper limit of normal
- Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and 30 days (for WOCBP) and 90 days (for men) after the last administration of study treatment. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.
- The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate of less than 1%), e.g. intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual abstinence
- The use of condoms by male patients is required unless the female partner is permanently sterile. Female subjects of childbearing potential must have a negative plasma pregnancy test upon study entry
- Must be able to tolerate MRI/CT scans
- Must be able to tolerate lumbar puncture and/or Ommaya taps
- Able to submit up to 20 unstained formalin-fixed, paraffin-embedded (FFPE) slides from the initial or most recent tissue diagnosis for correlative studies
Who cannot join
- 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%
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- 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
- Known history of infection with human immunodeficiency virus (HIV) or active stage of infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests, or any uncontrolled active systemic infection
- Patient underwent major systemic surgery ≤ 2 weeks prior to starting the trial treatment or who has not recovered from the side effects of such surgery, or who plan to have surgery within 2 weeks of the first dose of the study drug
- Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction
- Any life-threatening illness, medical condition including uncontrolled diabetes mellitus (DM), uncontrolled hypertension or organ system dysfunction that, in the opinion of the investigator, could compromise the subjects safety or put the study outcomes at undue risk
- Lactating or pregnant
- Excluded previous Therapies and medications:
- Concurrent use of warfarin or other vitamin K antagonists (need to be stopped 7 days prior to starting on trial drug)
- Concurrent use of a strong cytochrome P450 (CYP) 3A4/5 inhibitor and inducers (need to be stopped 2 weeks prior to starting on trial drug)
- Enzyme-inducing antiepileptic drugs (EIAED) need to be discontinued and switched to a non-EIAED 2 weeks prior to starting on trial drug)
- Patient requires more than 4 mg of dexamethasone daily or the equivalent
- Patient is using systemic immunosuppressant therapy, including cyclosporine A, tacrolimus, sirolimus, and other such medications, or chronic administration of > 5 mg/day or prednisone or the equivalent. Participants must be off of immunosuppressant therapy for at least 28 days prior to the first dose of the study drug
- Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of > 5 mg/day of prednisone) within 28 days of the first dose of study drug
Trial locations and contacts
3 sites in 1 country.
China3 sites, 3 recruiting
- Recruiting
Department of Hematology Nanfang Hospital, The Southern Medical University
Guandong, Guangdong, 510515
Ru Feng, M.D, +86 13725119762, ruth1626@hotmail.com
- Recruiting
Department of Medical Oncology, Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, 510060
Huiqiang Huang, +86 020 87343350, huanghq@sysucc.org.cn
Huiqiang Huang
- Recruiting
Guangdong 999 Brain Hospital
Guangzhou, Guangdong
Linbo Cai
About this study
Official title: Phase II Study of Combination Treatment of Methotrexate, Ibrutinib, and Temozolomide (MIT Regimen) in Patients With Newly Diagnosed Primary CNS Lymphoma
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.
Read the 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.
- Being tested
- Methotrexate, Ibrutinib, Temozolomide
- Keywords
- PCNSL, Newly Diagnosed
- Medical subject headings
- Lymphoma, Non-Hodgkin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethotrexateDrug
Also called MTX
Intravenous methotrexate at 3.5g/m2 (standard hydration/leucovorin support) will be given on day 1 of all cycles，for up to 4 cycles.
IbrutinibDrug
Also called Imbruvica
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.
TemozolomideDrug
Also called TMZ
Oral temozolomide will be given at 150mg/m2 from day1 to day 5 every 4 of all cycles，for up to 4 cycles.
| Study group | Role | What they receive |
|---|---|---|
| methotrexate, ibrutinib, and temozolomide (MIT regimen) | Experimental | 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. Receives: Drug: Methotrexate; Drug: Ibrutinib; Drug: Temozolomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
the overall response (complete response + partial response)，Investigator-Assessed
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)
Measured: up to 24 months
the toxicity profile of the ibrutinib/MTX/ temozolomide combination therapy
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.
Measured: up to 24 months
Secondary outcomes (4)
Complete response (CR) rate
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).
Measured: up to 24 months
Duration of response（DOR）
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.
Measured: up to 24 months
Progression-free survival (PFS)
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)
Measured: 1 year and 2 years
overall survival (OS)
1-year and 2-year OS rates.
Measured: 1 year and 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Aug 2020
- Study start10 Oct 2020
- Primary completion1 Sep 2022 (estimated)
- Study completion1 Jun 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Primary Central Nervous System LymphomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Single Group Assignment
- Masking
- None (open label)
- Enrolment
- 33 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Huiqiang Huang
- Sponsor type
- University, hospital or other
- Collaborators
- Guangdong 999 Brain Hospital, Nanfang Hospital, Southern Medical University, Xian-Janssen Pharmaceutical Ltd.
- Responsible party
- Sponsor-investigator, Huiqiang Huang, Sun Yat-sen University
- Investigators
- Huiqiang Huang, Professor, Principal investigator, Sun Yat-sen University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04514393
- Sponsor's protocol ID
- MIT
- Status last verified
- Apr 2022
- First submitted
- 11 Aug 2020
- Last updated
- 7 Apr 2022
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Study of Combination Treatment of Methotrexate, Ibrutinib, and Temozolomide (MIT Regimen) in Patients With Newly Diagnosed Primary CNS Lymphoma
- ClinicalTrials.gov ID
- NCT04514393
- Acronym / sponsor ID
- MIT
- Keywords
- PCNSL, Newly Diagnosed
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 33 participants (estimated)
- Lead sponsor
- Huiqiang HuangUniversity, hospital or other
- Collaborators
- Guangdong 999 Brain Hospital, Nanfang Hospital, Southern Medical University, Xian-Janssen Pharmaceutical Ltd.
- Study start
- 10 Oct 2020 (actual)
- Primary completion
- 1 Sep 2022 (estimated)
- Study completion
- 1 Jun 2024 (estimated)
- First posted
- 14 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Single Group Assignment
| Arm | Type | Receives |
|---|---|---|
| methotrexate, ibrutinib, and temozolomide (MIT regimen) | Experimental | Drug: Methotrexate, Drug: Ibrutinib, Drug: TemozolomideMethotrexate 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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- 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 ≤ 2.
- Life expectancy of > 3 months (in the opinion of the investigator).
- Adequate bone marrow and organ function shown by:
Key exclusion criteria (22 listed)
- Active concurrent malignancy requiring active therapy
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MethotrexateAlso: MTXIntravenous methotrexate at 3.5g/m2 (standard hydration/leucovorin support) will be given on day 1 of all cycles，for up to 4 cycles. | Drug | methotrexate, ibrutinib, and temozolomide (MIT regimen) |
| IbrutinibAlso: ImbruvicaOral 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. | Drug | methotrexate, ibrutinib, and temozolomide (MIT regimen) |
| TemozolomideAlso: TMZOral temozolomide will be given at 150mg/m2 from day1 to day 5 every 4 of all cycles，for up to 4 cycles. | Drug | methotrexate, ibrutinib, and temozolomide (MIT regimen) |
Primary outcome
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.
4 secondary outcomes
Complete response (CR) rate
Time frame: up to 24 months
Duration of response（DOR）
Time frame: up to 24 months
Progression-free survival (PFS)
Time frame: 1 year and 2 years
overall survival (OS)
Time frame: 1 year and 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Apr 2022.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Huiqiang Huang, Professor principal investigator
Sun Yat-sen University
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Methotrexate, Ibrutinib and Temozolomide in people with Primary Central Nervous System Lymphoma and PCNSL, run by Huiqiang Huang at 3 sites in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 7 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Huiqiang Huang, Professor (+86 020 87343350, huanghq@sysucc.org.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
the overall response (complete response + partial response)，Investigator-Assessed (time frame: up to 24 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Apr 2022.