Clinical trial NCT03123718: High-dose Intravenous Methotrexate Versus Intrathecal Methotrexate for Central Nervous System Prophylaxis in DLBCL
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: DLBCL
Keywords: methotrexate
Lead sponsor: Chonnam National University Hospital
Sponsor class: OTHER
Collaborators: name: Consortium for Improving Survival of Lymphoma
First posted: 2017-04-21
Enrollment: 205
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Cumulative incidence of CNS relapse
timeFrame: 2 year
Secondary outcomes:
measure: Toxicity
timeFrame: 2 year
measure: Progression-free survival (PFS)
timeFrame: 2 year
Other outcomes:
Locations:
city: Hwasun-gun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Jeollanam-do
Study officials:
References: