Trial for Patients With Newly Diagnosed Primary Central Nervous System (CNS) Lymphoma

NCT ID: NCT01011920

Last Updated: 2017-08-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 126 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-11-30
• Study Completion Date: 2017-03-31

Brief Summary

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.

Conditions

Central Nervous System Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Methotrexate

Intervention Type: DRUG

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.

Ara-C

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

Ara-C

Intervention Type: DRUG

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

Rituximab

Intervention Type: DRUG

Rituximab 375 mg/m2 conventional infusion on day - 5 \& 0 every 3 weeks for a maximum of 4 cycles

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

Group Type: EXPERIMENTAL

Ara-C

Intervention Type: DRUG

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

Rituximab

Intervention Type: DRUG

Rituximab 375 mg/m2 conventional infusion on day - 5 \& 0 every 3 weeks for a maximum of 4 cycles

Thiotepa

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

radiotherapy

Intervention Type: RADIATION

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.

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

Group Type: EXPERIMENTAL

Thiotepa

Intervention Type: DRUG

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

BCNU

Intervention Type: DRUG

BCNU 400 mg/m2 in 500 ml saline sol 1-hr inf. day -6

APBSCT

Intervention Type: OTHER

Autologous peripheral blood stem cell transplant (APBSCT)

Interventions

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.

Intervention Type: 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

Intervention Type: DRUG

Rituximab

Rituximab 375 mg/m2 conventional infusion on day - 5 \& 0 every 3 weeks for a maximum of 4 cycles

Intervention Type: 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

Intervention Type: DRUG

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.

Intervention Type: RADIATION

BCNU

BCNU 400 mg/m2 in 500 ml saline sol 1-hr inf. day -6

Intervention Type: DRUG

APBSCT

Autologous peripheral blood stem cell transplant (APBSCT)

Intervention Type: OTHER

Other Intervention Names

Cytarabine; MabThera; Carmustine

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

International Extranodal Lymphoma Study Group (IELSG)

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andrés JM Ferreri, MD

Role: STUDY_CHAIR

San Raffaele H Scientific Institute, Milan, Italy

Gerald Illerhaus, MD

Role: STUDY_CHAIR

University Medical Center, Freiburg, Germany

Emanuele Zucca, MD

Role: PRINCIPAL_INVESTIGATOR

IOSI, Bellinzona, Switzerland

Locations

University Hospital

Aachen, , Germany

Universitätsklinikum Erlangen

Erlangen, , Germany

"Klinik für Hämatologie Universitätsklinikum Essen"

Essen, , Germany

Uniklinik Freiburg

Freiburg im Breisgau, , Germany

Universitätskrankenhaus Hamburg-Eppendorf

Hamburg, , Germany

Friedrich Schiller Universitaet Jena

Jena, , Germany

Johannes Gutenberg Universität Mainz

Mainz, , Germany

Technische Universität in München

München, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

A.O. SS. Antonio e Biagio e Cesare Arrigo

Alessandria, , Italy

Spedali Civili

Brescia, , Italy

San Raffaele H Scientific Institute

Milan, , Italy

Ospedale Umberto I

Nocera Inferiore, , Italy

Ospedale Civile S.Spirito

Pescara, , Italy

Arcispedale Santa Maria Nuova

Reggio Emilia, , Italy

Istituto Nazionale dei Tumori Regina Elena

Roma, , Italy

Università degli Studi La Sapienza

Roma, , Italy

Humanitas

Rozzano, , Italy

Ospedale Maggiore S. Giovanni Battista

Torino, , Italy

Policlinico G.B. Rossi

Verona, , Italy

IOSI - Oncology Institute of Southern Switzerland

Bellinzona, , Switzerland

Nottingham City Hospital

Nottingham, , United Kingdom

Queen's Hospital

Romford, , United Kingdom

Countries

Germany; Italy; Switzerland; United Kingdom

References

Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosee P, Binder M, Fabbri A, Torri V, Minacapelli E, Falautano M, Ilariucci F, Ambrosetti A, Roth A, Hemmaway C, Johnson P, Linton KM, Pukrop T, Sonderskov Gorlov J, Balzarotti M, Hess G, Keller U, Stilgenbauer S, Panse J, Tucci A, Orsucci L, Pisani F, Levis A, Krause SW, Schmoll HJ, Hertenstein B, Rummel M, Smith J, Pfreundschuh M, Cabras G, Angrilli F, Ponzoni M, Deckert M, Politi LS, Finke J, Reni M, Cavalli F, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group (IELSG). Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol. 2017 Nov;4(11):e510-e523. doi: 10.1016/S2352-3026(17)30174-6. Epub 2017 Oct 17.

Reference Type: DERIVED

PMID: 29054815 (View on PubMed)

Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosee PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Ruda R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gorlov JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group (IELSG). Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016 May;3(5):e217-27. doi: 10.1016/S2352-3026(16)00036-3. Epub 2016 Apr 6.

Reference Type: DERIVED

PMID: 27132696 (View on PubMed)

Other Identifiers

IELSG32

Identifier Type: -

Identifier Source: org_study_id