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

Chonnam National University

Status and phase: Unknown; Phase 3

Conditions: DLBCL

Treatments: Drug: Intrathecal methotrexate; Drug: High-dose intravenous methotrexate

Study type: Interventional

Funder types: Other

Identifiers

NCT03123718

HDMTX

Details and patient eligibility

About

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.

Enrollment: 205 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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205 participants in 2 patient groups

Intrathecal Methotrexate

Other group

Treatment:

Drug: Intrathecal methotrexate

High-dose Intravenous Methotrexate

Active Comparator group

Treatment:

Drug: High-dose intravenous methotrexate