High-dose Intravenous Methotrexate Versus Intrathecal Methotrexate for Central Nervous System Prophylaxis in DLBCL

Prospective, Multicenter, Randomized ,Open-labeled, Phase III Study Comparing High-dose Intravenous Methotrexate Versus Intrathecal Methotrexate for the Prophylaxis of Central Nervous System Relapse in Diffuse Large B Cell Lymphoma

The outcome of patients with central nervous system (CNS) relapse in DLBCL is poor, with median survival times of 2-5 months. This fatal prognosis necessitates CNS prevention in a subgroup of patients with a high risk of CNS relapse.

Intrathecal methotrexate (ITMTX) has traditionally been used, although its efficacy for CNS prophylaxis is contradictory. High-dose intravenous methotrexate (IVMTX) has been suggested as an alternative approach. Considering the lack of evidence supporting the role of ITMTX, the investigators propose to compare the efficacy of ITMTX and IVMTX for prophylaxis of CNS relapse in a subgroup of patients with DLBCL at a high risk for CNS relapse.

Study Overview

• Status: Unknown
• Conditions: DLBCL
• Intervention / Treatment: Drug: Intrathecal methotrexate; Drug: High-dose intravenous methotrexate

• Study Type: Interventional
• Enrollment (Anticipated): 205
• Phase: Phase 3

Contacts and Locations

Study Locations

• Korea, Republic of
  • Jeollanam-do
    • Hwasun-gun, Jeollanam-do, Korea, Republic of, 519-809
      • Chonnam National University Hwasun Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged ≥18 years <80
• Newly diagnosed, histologically confirmed DLBCL

• High-risk of CNS recurrence at diagnosis:

  1. Age-adjusted IPI (aaIPI) ≥2 or IPI ≥4 with extranodal involvement of >1 site plus serum lactate dehydrogenase (LDH) > normal OR
  2. Involvement of high-risk locations: bone marrow, nasal or paranasal sinuses, testis, epidural disease (paravertebral or vertebra), breast, adrenal or kidney
• Estimated life expectancy of more than 90 days
• Performance status (ECOG) ≤ 2
• Written informed consent

Exclusion Criteria:

• Psychiatric or mental disorder which make the patient unable to give an informed consent and/or adhere to the protocol

• DLBCL or following subtypes:

  1. Primary mediastinal large B-cell lymphoma
  2. Grey zone lymphoma)
  3. Primary cutaneous DLBCL
• Previous immunochemotherapeutic treatment for DLBCL other than short-term use of corticosteroids (≤ 8 days before randomization)
• Previous radiotherapy
• CNS involvement of DLBCL at diagnosis
• HIV positive
• Any contraindication for application of RCHOP or high dose methotrexate

• Any of following laboratory results

  1. Absolute neutrophil count < 1,500 cells/mm3 (1.5 x 109/L),
  2. Platelet count < 100,000/mm3 (100 x 109/L), or < 75,000 /mm3 in patients with bone marrow involvement,
  3. Serum aspartate transaminase or serum alanine transaminase ≥3.0 x upper limit of normal (ULN),
  4. Serum total bilirubin > 2 x ULN (with the exception of hemolytic anemia),
• Serum creatinine >2.0 x ULN or creatinine clearance <50 mL/min
• Active cancer except curable basal cell carcinoma, cervical cancer in situ, and/or papillary thyroid cancer during the last five years
• Ejection fraction < 45% on echocardiography
• Uncontrolled active hepatitis
• Pregnancy or breast-feeding
• Men and women of reproductive potential no agreeing to use an acceptable method of birth control during treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Intrathecal Methotrexate	Drug: Intrathecal methotrexate; Intrathecal administration of 2nd, 3rd, and 4th doses of methotrexate 15 mg and hydrocortisone 50mg on day 2 or 3 of 2nd, 3rd, and 4th cycles of immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP), respectively.
Active Comparator: High-dose Intravenous Methotrexate	Drug: High-dose intravenous methotrexate; Intravenous administration of 1st and 2nd doses of methotrexate 3g/m2 on day 15 of 2nd and 6th cycles of immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP), respectively. * Dose of intravenous methotrexate will be reduced to 2g/m2 for patients aged >70 years.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of CNS relapse	The rate of relapse will be analyzed by the cumulative incidence method	2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	Toxicity will be graded according to NCI-CTCAE v.4.03	2 year
Progression-free survival (PFS)	PFS will be calculated from randomization to the date of CNS relapse and/or systemic disease progression, death, or last follow-up, as appropriate.	2 year

Collaborators and Investigators

• Sponsor: Chonnam National University Hospital
• Collaborators: Consortium for Improving Survival of Lymphoma

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2017
• Primary Completion (Anticipated): June 30, 2021
• Study Completion (Anticipated): June 30, 2021

Study Registration Dates

• First Submitted: April 18, 2017
• First Submitted That Met QC Criteria: April 18, 2017
• First Posted (Actual): April 21, 2017

Study Record Updates

• Last Update Posted (Actual): April 24, 2017
• Last Update Submitted That Met QC Criteria: April 21, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: methotrexate
• Additional Relevant MeSH Terms: 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; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: HDMTX

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