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

Primary Purpose

Central Nervous System Lymphoma

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Methotrexate
Ara-C
Rituximab
Thiotepa
radiotherapy
BCNU
APBSCT
Sponsored by
International Extranodal Lymphoma Study Group (IELSG)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Central Nervous System Lymphoma focused on measuring newly diagnosed primary central nervous system lymphoma

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • University Hospital
  • Universitätsklinikum Erlangen
  • "Klinik für Hämatologie Universitätsklinikum Essen"
  • Uniklinik Freiburg
  • Universitätskrankenhaus Hamburg-Eppendorf
  • Friedrich Schiller Universitaet Jena
  • Johannes Gutenberg Universität Mainz
  • Technische Universität in München
  • Universitätsklinikum Ulm
  • A.O. SS. Antonio e Biagio e Cesare Arrigo
  • Spedali Civili
  • San Raffaele H Scientific Institute
  • Ospedale Umberto I
  • Ospedale Civile S.Spirito
  • Arcispedale Santa Maria Nuova
  • Istituto Nazionale dei Tumori Regina Elena
  • Università degli Studi La Sapienza
  • Humanitas
  • Ospedale Maggiore S. Giovanni Battista
  • Policlinico G.B. Rossi
  • IOSI - Oncology Institute of Southern Switzerland
  • Nottingham City Hospital
  • Queen's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

MTX+ AraC

Ara-C +Rituximab

Ara-C + rituximab+thiotepa

WBRT 36 Gy +/- boost 9 Gy

BCNU + Thiotepa + APBSCT

Arm Description

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

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

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

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.

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

Outcomes

Primary Outcome Measures

response rate after primary chemotherapy and 2 years failure free survival at second randomization

Secondary Outcome Measures

safety, as acute and long-term toxicity
overall survival

Full Information

First Posted
November 9, 2009
Last Updated
August 22, 2017
Sponsor
International Extranodal Lymphoma Study Group (IELSG)
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1. Study Identification

Unique Protocol Identification Number
NCT01011920
Brief Title
Trial for Patients With Newly Diagnosed Primary Central Nervous System (CNS) Lymphoma
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 Type
Interventional

2. Study Status

Record Verification Date
July 2016
Overall Recruitment Status
Completed
Study Start Date
November 2009 (undefined)
Primary Completion Date
March 2015 (Actual)
Study Completion Date
March 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
International Extranodal Lymphoma Study Group (IELSG)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Central Nervous System Lymphoma
Keywords
newly diagnosed primary central nervous system lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
126 (Actual)

8. Arms, Groups, and Interventions

Arm Title
MTX+ AraC
Arm Type
Experimental
Arm Description
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
Arm Title
Ara-C +Rituximab
Arm Type
Experimental
Arm Description
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
Arm Title
Ara-C + rituximab+thiotepa
Arm Type
Experimental
Arm Description
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
Arm Title
WBRT 36 Gy +/- boost 9 Gy
Arm Type
Experimental
Arm Description
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.
Arm Title
BCNU + Thiotepa + APBSCT
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Intervention Description
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
Intervention Name(s)
Ara-C
Other Intervention Name(s)
Cytarabine
Intervention Description
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
Intervention Name(s)
Rituximab
Other Intervention Name(s)
MabThera
Intervention Description
Rituximab 375 mg/m2 conventional infusion on day - 5 & 0 every 3 weeks for a maximum of 4 cycles
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Intervention Description
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
Radiation
Intervention Name(s)
radiotherapy
Intervention Description
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
Drug
Intervention Name(s)
BCNU
Other Intervention Name(s)
Carmustine
Intervention Description
BCNU 400 mg/m2 in 500 ml saline sol 1-hr inf. day -6
Intervention Type
Other
Intervention Name(s)
APBSCT
Intervention Description
Autologous peripheral blood stem cell transplant (APBSCT)
Primary Outcome Measure Information:
Title
response rate after primary chemotherapy and 2 years failure free survival at second randomization
Time Frame
3 months, 2 years
Secondary Outcome Measure Information:
Title
safety, as acute and long-term toxicity
Time Frame
Throughout all the active treatment period
Title
overall survival
Time Frame
From entry onto trial until death for any cause

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrés JM Ferreri, MD
Organizational Affiliation
San Raffaele H Scientific Institute, Milan, Italy
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Gerald Illerhaus, MD
Organizational Affiliation
University Medical Center, Freiburg, Germany
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Emanuele Zucca, MD
Organizational Affiliation
IOSI, Bellinzona, Switzerland
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital
City
Aachen
Country
Germany
Facility Name
Universitätsklinikum Erlangen
City
Erlangen
Country
Germany
Facility Name
"Klinik für Hämatologie Universitätsklinikum Essen"
City
Essen
Country
Germany
Facility Name
Uniklinik Freiburg
City
Freiburg
Country
Germany
Facility Name
Universitätskrankenhaus Hamburg-Eppendorf
City
Hamburg
Country
Germany
Facility Name
Friedrich Schiller Universitaet Jena
City
Jena
Country
Germany
Facility Name
Johannes Gutenberg Universität Mainz
City
Mainz
Country
Germany
Facility Name
Technische Universität in München
City
München
Country
Germany
Facility Name
Universitätsklinikum Ulm
City
Ulm
Country
Germany
Facility Name
A.O. SS. Antonio e Biagio e Cesare Arrigo
City
Alessandria
Country
Italy
Facility Name
Spedali Civili
City
Brescia
Country
Italy
Facility Name
San Raffaele H Scientific Institute
City
Milan
Country
Italy
Facility Name
Ospedale Umberto I
City
Nocera Inferiore
Country
Italy
Facility Name
Ospedale Civile S.Spirito
City
Pescara
Country
Italy
Facility Name
Arcispedale Santa Maria Nuova
City
Reggio Emilia
Country
Italy
Facility Name
Istituto Nazionale dei Tumori Regina Elena
City
Roma
Country
Italy
Facility Name
Università degli Studi La Sapienza
City
Roma
Country
Italy
Facility Name
Humanitas
City
Rozzano
Country
Italy
Facility Name
Ospedale Maggiore S. Giovanni Battista
City
Torino
Country
Italy
Facility Name
Policlinico G.B. Rossi
City
Verona
Country
Italy
Facility Name
IOSI - Oncology Institute of Southern Switzerland
City
Bellinzona
ZIP/Postal Code
6500
Country
Switzerland
Facility Name
Nottingham City Hospital
City
Nottingham
Country
United Kingdom
Facility Name
Queen's Hospital
City
Romford
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
29054815
Citation
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.
Results Reference
derived
PubMed Identifier
27132696
Citation
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.
Results Reference
derived

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

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