Ibrutinib With Methotrexate and Temozolomide for Patients With Newly Diagnosed Primary CNS Lymphoma

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.

Study Overview

• Status: Recruiting
• Conditions: Primary Central Nervous System Lymphoma; Non Hodgkin Lymphoma; PCNSL
• Intervention / Treatment: Drug: Methotrexate; Drug: Ibrutinib; Drug: Temozolomide

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 Type: Interventional
• Enrollment (Anticipated): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guandong, Guangdong, China, 510515
      • Recruiting
      • Department of Hematology Nanfang Hospital, The Southern Medical University
      • Contact: Ru Feng, M.D; Phone Number: +86 13725119762; Email: ruth1626@hotmail.com
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Department of Medical Oncology, Sun Yat-Sen University Cancer Center
      • Principal Investigator: Huiqiang Huang
      • Contact: Huiqiang Huang; Phone Number: +86 020 87343350; Email: huanghq@sysucc.org.cn
      • Sub-Investigator: Xiaoxiao Wang
    • Guangzhou, Guangdong, China
      • Recruiting
      • Guangdong 999 Brain Hospital
      • Contact: Linbo Cai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 ≤ 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
  • 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

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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Drug: Methotrexate; 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 Names: MTX; Drug: Ibrutinib; 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 Names: Imbruvica; Drug: Temozolomide; Oral temozolomide will be given at 150mg/m2 from day1 to day 5 every 4 of all cycles，for up to 4 cycles.; Other Names: TMZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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.	up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	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)	1 year and 2 years
overall survival (OS)	1-year and 2-year OS rates.	1 year and 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Describe the tumor mutation profile by NGS	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.	up to 24 months
Relationship between prognostic and gene mutation in patients with PCNSL	Will be correlated with treatment response, mutational analysis using next-generation sequencing, and characterization of aberrant gene expression in PCNSL samples	up to 24 months

Collaborators and Investigators

• Sponsor: Huiqiang Huang
• Collaborators: Xian-Janssen Pharmaceutical Ltd.; Nanfang Hospital of Southern Medical University; Guangdong 999 Brain Hospital
• Investigators: Principal Investigator: Huiqiang Huang, professor, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2020
• Primary Completion (Anticipated): September 1, 2022
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: August 11, 2020
• First Submitted That Met QC Criteria: August 12, 2020
• First Posted (Actual): August 14, 2020

Study Record Updates

• Last Update Posted (Actual): April 7, 2022
• Last Update Submitted That Met QC Criteria: April 6, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Newly Diagnosed; PCNSL
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Temozolomide; Methotrexate
• Other Study ID Numbers: MIT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No