Trial for Patients With Newly Diagnosed Primary Central Nervous System (CNS) Lymphoma
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ClinicalTrials.gov Identifier: NCT01011920 |
Recruitment Status :
Completed
First Posted : November 11, 2009
Last Update Posted : August 23, 2017
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This is a multicenter open label randomized phase II trial.
Enrolled Primary Central Nervous System Lymphoma (PCNSL) patients will be stratified according to the IELSG score and randomized to receive one of the follows as primary chemotherapy:
- Arm A: Methotrexate (MTX) + Cytarabine (Ara-C)
- Arm B: MTX + Ara-C + rituximab
- Arm C: MTX + Ara-C + rituximab + thiotepa.
Chemotherapy will be administered every three weeks. The maximum number of chemotherapy induction courses will be 4. Patients in Stable Disease (SD) or better after two courses will receive two more courses of the same primary chemotherapy regimen. Stem-cells harvest will be performed in the three arms after the second course. After 4 courses response assessment will be performed.
Patients who will not achieve SD or better after the 4th course, as well as those who will experience Progressive Disease (PD) at any time and those who will not achieve a sufficient stem cell harvest, will receive Whole Brain Radiation Therapy (WBRT) 36-40 Gy +/- tumor bed boost of 9 Gy.
Patients who will achieve SD or better after the 4th course will be stratified according to objective response to primary chemotherapy and to primary chemotherapy regimen and randomly allocated to receive as consolidation therapy one of the follows:
- Arm D: WBRT 36 Gy +/- boost 9 Gy
- Arm E: Carmustine (BCNU) + Thiotepa + Autologous Peripheral Blood Stem Cell Transplant (APBSCT) Patients in Complete Response (CR) after WBRT or APBSCT will remain in follow-up. Patients who will not achieve a CR after WBRT will be managed according to physician's preferences. Patients who will not achieve a CR after APBSCT will be referred to WBRT.
Condition or disease | Intervention/treatment | Phase |
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Central Nervous System Lymphoma | Drug: Methotrexate Drug: Ara-C Drug: Rituximab Drug: Thiotepa Radiation: radiotherapy Drug: BCNU Other: APBSCT | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 126 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Randomized Phase II Trial On Primary Chemotherapy With High-Dose Methotrexate And High-Dose Cytarabine With Or Without Thiotepa, And With Or Without Rituximab, Followed By Brain Irradiation Vs. High-Dose Chemotherapy Supported By Autologous Stem Cells Transplantation For Immunocompetent Patients With Newly Diagnosed Primary CNS Lymphoma |
Study Start Date : | November 2009 |
Actual Primary Completion Date : | March 2015 |
Actual Study Completion Date : | March 2017 |

Arm | Intervention/treatment |
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Experimental: MTX+ AraC
Arm A Methotrexate 3.5 g/m2 (0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion) d 1 Cytarabine 2 g/m2 1 hr infusion, twice a day (every 12 hs.) d 2 - 3
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Drug: Methotrexate
Methotrexate 3.5 g/m2 (0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion) on day 1, every 3 weeks for a maximum of 4 courses. Drug: Ara-C Cytarabine 2 g/m2 (1 hr infusion, twice a day every 12 hours), on d 2 - 3 every 3 weeks for a maximum of 4 courses
Other Name: Cytarabine |
Experimental: Ara-C +Rituximab
Arm B Rituximab 375 mg/m2 conventional infusion d -5 & 0 Methotrexate 3.5 g/m2 0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion d 1 Cytarabine 2 g/m2 1 hr infusion, twice a day (every 12 hs.) d 2 - 3
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Drug: Ara-C
Cytarabine 2 g/m2 (1 hr infusion, twice a day every 12 hours), on d 2 - 3 every 3 weeks for a maximum of 4 courses
Other Name: Cytarabine Drug: Rituximab Rituximab 375 mg/m2 conventional infusion on day - 5 & 0 every 3 weeks for a maximum of 4 cycles
Other Name: MabThera |
Experimental: Ara-C + rituximab+thiotepa
Arm C Rituximab 375 mg/m2 conventional infusion d -5 & 0 Methotrexate 3.5 g/m2 0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion d 1 Cytarabine 2 g/m2 1 hr infusion, twice a day (every 12 hs.) d 2 - 3 Thiotepa 30 mg/m2 30 min. Infusion d 4
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Drug: Ara-C
Cytarabine 2 g/m2 (1 hr infusion, twice a day every 12 hours), on d 2 - 3 every 3 weeks for a maximum of 4 courses
Other Name: Cytarabine Drug: Rituximab Rituximab 375 mg/m2 conventional infusion on day - 5 & 0 every 3 weeks for a maximum of 4 cycles
Other Name: MabThera Drug: Thiotepa ARM C: Thiotepa 30 mg/m2 (30 min. Infusion) on day 4 every 3 weeks for a maximum of 4 courses ARM E: Thiotepa 5 mg/kg in 250 ml saline sol 2-hr inf. every 12 hrs days -5 & -4 |
Experimental: WBRT 36 Gy +/- boost 9 Gy
ARM D: WBRT with 36 Gy in the case of CR to primary chemotherapy or the same WBRT dose followed by a tumor-bed boost of 9 Gy with 1-2 cm of margin surrounding enhanced residual lesion (total tumor-bed dose 45 Gy) in patients who achieved a PR or SD after primary chemotherapy. Photons of 4-10 Mev, 180 cGy per day, 5 weekly fractions.
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Radiation: radiotherapy
Photons of 4-10 Mev, 180 cGy per day, 5 weekly fractions. Whole-brain will be irradiated by two opposite lateral fields including the first two cervical vertebras and the posterior two thirds of the orbits, which must be shielded after 30 Gy (after 36 Gy in the case of evident intraocular disease at diagnosis). Tumor-bed (boost or partial-brain RT) will be irradiated by 2 to 4 isocentric treatment fields based on tumor location, with all portals treated per each RT session. |
Experimental: BCNU + Thiotepa + APBSCT
Arm E BCNU 400 mg/m2 in 500 ml saline sol 1-hr inf. day -6 Thiotepa 5 mg/kg in 250 ml saline sol 2-hr inf. every 12 hrs days -5 & -4 Reinfusion of PBSC ≥5 x 106 CD34+ cells/kg day 0
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Drug: Thiotepa
ARM C: Thiotepa 30 mg/m2 (30 min. Infusion) on day 4 every 3 weeks for a maximum of 4 courses ARM E: Thiotepa 5 mg/kg in 250 ml saline sol 2-hr inf. every 12 hrs days -5 & -4 Drug: BCNU BCNU 400 mg/m2 in 500 ml saline sol 1-hr inf. day -6
Other Name: Carmustine Other: APBSCT Autologous peripheral blood stem cell transplant (APBSCT) |
- response rate after primary chemotherapy and 2 years failure free survival at second randomization [ Time Frame: 3 months, 2 years ]
- safety, as acute and long-term toxicity [ Time Frame: Throughout all the active treatment period ]
- overall survival [ Time Frame: From entry onto trial until death for any cause ]

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Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Histological or cytological assessed diagnosis of non-Hodgkin's lymphoma.
- Diagnostic sample obtained by stereotactic or surgical biopsy, Cerebrospinal Fluid (CSF) cytology examination or vitrectomy.
- Disease exclusively localized into the central nervous system, CSF, cranial nerves or eyes.
- At least one measurable lesion.
- Previously untreated patients (previous or ongoing steroid therapy admitted).
- Age 18-65 years (with ECOG Performance Status 0-3) or 66-70 (with ECOG Performance Status 0-2).
- Adequate bone marrow, renal, cardiac, and hepatic function.
- Sexually active patients of childbearing potential agreeing in implementing adequate contraceptive measures during study participation.
- Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
- Patient-signed informed consent obtained before registration.
Exclusion Criteria:
- Patients with lymphomatous lesions outside the CNS.
- Patients with a previous non-Hodgkin lymphoma at any time.
- Previous or concurrent malignancies with the exception of surgically cured carcinoma in-situ of the cervix, carcinoma of the skin or other cancers without evidence of disease at least from 5 years.
- HBsAg and HCV positivity.
- HIV infection, previous organ transplantation or other clinically evident form of immunodeficiency.
- Concurrent treatment with other experimental drugs.
- Concurrent Pregnancy or lactation.
- Patients not agreeing to take adequate contraceptive measures during the study.
- Symptomatic coronary artery disease, cardiac arrhythmias uncontrolled with medication or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease).

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01011920

Study Chair: | Andrés JM Ferreri, MD | San Raffaele H Scientific Institute, Milan, Italy | |
Study Chair: | Gerald Illerhaus, MD | University Medical Center, Freiburg, Germany | |
Principal Investigator: | Emanuele Zucca, MD | IOSI, Bellinzona, Switzerland |
Responsible Party: | International Extranodal Lymphoma Study Group (IELSG) |
ClinicalTrials.gov Identifier: | NCT01011920 |
Other Study ID Numbers: |
IELSG32 |
First Posted: | November 11, 2009 Key Record Dates |
Last Update Posted: | August 23, 2017 |
Last Verified: | July 2016 |
newly diagnosed primary central nervous system lymphoma |
Lymphoma Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Cytarabine Rituximab Methotrexate Thiotepa Carmustine Antineoplastic Agents, Immunological Antineoplastic Agents Immunologic Factors |
Physiological Effects of Drugs Antirheumatic Agents Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Dermatologic Agents Enzyme Inhibitors Folic Acid Antagonists Immunosuppressive Agents Nucleic Acid Synthesis Inhibitors Antiviral Agents Anti-Infective Agents |