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

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

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.

Study Overview

• Status: Completed
• Conditions: Central Nervous System Lymphoma
• Intervention / Treatment: Drug: Methotrexate; Drug: Ara-C; Drug: Rituximab; Drug: Thiotepa; Radiation: radiotherapy; Drug: BCNU; Other: APBSCT

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany
    • University Hospital
  • Erlangen, Germany
    • Universitätsklinikum Erlangen
  • Essen, Germany
    • "Klinik für Hämatologie Universitätsklinikum Essen"
  • Freiburg, Germany
    • Uniklinik Freiburg
  • Hamburg, Germany
    • Universitatskrankenhaus Hamburg-Eppendorf
  • Jena, Germany
    • Friedrich Schiller Universitaet Jena
  • Mainz, Germany
    • Johannes Gutenberg Universitat Mainz
  • München, Germany
    • Technische Universität in München
  • Ulm, Germany
    • Universitätsklinikum Ulm
• Italy
  • Alessandria, Italy
    • A.O. SS. Antonio e Biagio e Cesare Arrigo
  • Brescia, Italy
    • Spedali Civili
  • Milan, Italy
    • San Raffaele H Scientific Institute
  • Nocera Inferiore, Italy
    • Ospedale Umberto I
  • Pescara, Italy
    • Ospedale Civile S.Spirito
  • Reggio Emilia, Italy
    • Arcispedale Santa Maria Nuova
  • Roma, Italy
    • Istituto Nazionale dei Tumori Regina Elena
  • Roma, Italy
    • Università degli Studi La Sapienza
  • Rozzano, Italy
    • Humanitas
  • Torino, Italy
    • Ospedale Maggiore S. Giovanni Battista
  • Verona, Italy
    • Policlinico G.B. Rossi
• Switzerland
  • Bellinzona, Switzerland, 6500
    • IOSI - Oncology Institute of Southern Switzerland
• United Kingdom
  • Nottingham, United Kingdom
    • Nottingham City Hospital
  • Romford, United Kingdom
    • Queen's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	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 Names: 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	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 Names: Cytarabine; Drug: Rituximab; Rituximab 375 mg/m2 conventional infusion on day - 5 & 0 every 3 weeks for a maximum of 4 cycles; Other Names: 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	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 Names: Cytarabine; Drug: Rituximab; Rituximab 375 mg/m2 conventional infusion on day - 5 & 0 every 3 weeks for a maximum of 4 cycles; Other Names: 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.	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	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 Names: Carmustine; Other: APBSCT; Autologous peripheral blood stem cell transplant (APBSCT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
response rate after primary chemotherapy and 2 years failure free survival at second randomization	3 months, 2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
safety, as acute and long-term toxicity	Throughout all the active treatment period
overall survival	From entry onto trial until death for any cause

Collaborators and Investigators

• Sponsor: International Extranodal Lymphoma Study Group (IELSG)
• Investigators: 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

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: November 9, 2009
• First Submitted That Met QC Criteria: November 10, 2009
• First Posted (Estimate): November 11, 2009

Study Record Updates

• Last Update Posted (Actual): August 23, 2017
• Last Update Submitted That Met QC Criteria: August 22, 2017
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: newly diagnosed primary central nervous system lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Rituximab; Cytarabine; Methotrexate; Thiotepa; Carmustine
• Other Study ID Numbers: IELSG32