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

Conditions

Central Nervous System Lymphoma

Keywords

newly diagnosed primary central nervous system lymphoma

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.

Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosée 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, Sønderskov Gørløv 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).

2017-10-17258 citations

10.1016/s2352-3026(17)30174-6

Effects on Survival and Neurocognitive Functions of Whole-Brain Radiotherapy (WBRT) and Autologous Stem Cell Transplantation (ASCT) as Consolidation Options after High-Dose Methotrexate-Based Chemoimmunotherapy in Patients with Newly Diagnosed Primary CNS Lymphoma (PCNSL): Results of the Second Randomization of the IELSG32 Trial

Andrés J.M. Ferreri, Kate Cwynarski, Elisa Jacobsen Pulczynski, Christopher P. Fox, Elisabeth Schorb et al. (44 authors)

Blood2016-12-022 citations

10.1182/blood.v128.22.511.511

High-dose chemotherapy and autologous stem cell transplant compared with conventional chemotherapy for consolidation in newly diagnosed primary CNS lymphoma--a randomized phase III trial (MATRix).

Schorb E, Finke J, Ferreri AJ, Ihorst G, Mikesch K, Kasenda B, Fritsch K, Fricker H, Burger E, Grishina O, Valk E, Zucca E, Illerhaus G.

2016-04-2148 citations

10.1186/s12885-016-2311-4

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.

Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gørløv 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).

2016-04-06427 citations

10.1016/s2352-3026(16)00036-3

Interventions

DRUGMethotrexate

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.

DRUGAra-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

DRUGRituximab

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

DRUGThiotepa

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

RADIATIONradiotherapy

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.

DRUGBCNU

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

OTHERAPBSCT

Autologous peripheral blood stem cell transplant (APBSCT)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

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).

Design outcomes

Primary

Measure	Time frame	Description
Complete Remission Rate After Primary Chemotherapy	3 months after treatment start	Percentage of patients with complete remission after 3 month of treatment. Percentage values are rounded to whole numbers.
2 Years Failure Free Survival (FFS) After Second Randomization	Every 3 weeks during treatment and every 3 months thereafter up to 2 years from study entry	Percentage of patients alive and free from disease progression, relapse, need for new treatment, after 2 years from study entry. Percentage values are rounded to whole numbers.

Secondary

Measure	Time frame	Description
2 Years Failure Free Survival (FFS)	Every 3 weeks during treatment and every 3 months thereafter up to 2 years from study entry	Percentage of patients alive and free from disease progression, relapse, need for new treatment, after 2 years from study entry any cause. Percentage values are rounded to whole numbers.
2 Year Overall Survival (OS)	From study entry until 2 years after	Percentage of patients alive after 2 years from study entry. Percentage values are rounded to whole numbers.

Countries

Denmark, Germany, Italy, Switzerland, United Kingdom

Contacts

STUDY_CHAIRAndrés JM Ferreri, MD

San Raffaele H Scientific Institute, Milan, Italy

STUDY_CHAIRGerald Illerhaus, MD

University Medical Center, Freiburg, Germany

PRINCIPAL_INVESTIGATOREmanuele Zucca, MD

IOSI, Bellinzona, Switzerland

Participant flow

Recruitment details

Two hundreds and twenty seven patients were enrolled and treated in the IELSG32 study. Eight patients were excluded (five from arm B and three from arm C) because of misdiagnosis, systemic lymphoma, or concomitant cancer.

Pre-assignment details

At the end of first randomization 167 patients with responsive or stable disease were observed . Eighteen patients experienced PD before the second randomization, 12 were deemed unfit, and 15 had no harvest. Consequently, 122 patients were eligible and assessable for second randomization. Four patients refused the second randomization, leaving 59 patients allocated to Arm D and 59 to Arm E. Of these, five patients refused consolidation resulting in 113 patients proceeding

Baseline characteristics

Characteristic	—
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	69 Participants
Age, Continuous	57 years
Deep lesions Deep lesions	52 Participants
Deep lesions No deep lesions	17 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG 0-1	48 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG>1	27 Participants
Increased cerebrospinal fluid (CSF) protein Increased CSF protein	35 Participants
Increased cerebrospinal fluid (CSF) protein No increased CSF protein	18 Participants
Increased cerebrospinal fluid (CSF) protein Not recorded	22 Participants
Increased LDH Increased LDH	37 Participants
Increased LDH No increased LDH	50 Participants
International Extranodal Lymphoma Study Group (IELSG) risk score High Risk	42 Participants
International Extranodal Lymphoma Study Group (IELSG) risk score Intermediate Risk	47 Participants
International Extranodal Lymphoma Study Group (IELSG) risk score Low Risk	12 Participants
Intraocular disease Intraocular disease	1 Participants
Intraocular disease No intraocular disease	212 Participants
Meningeal involvement Meningeal involvement	11 Participants
Meningeal involvement No meningeal involvement	128 Participants
Meningeal involvement Not recorded	16 Participants
Multiple lesions Multiple lesions	40 Participants
Multiple lesions No multiple lesions	93 Participants
Region of Enrollment Denmark	5 participants
Region of Enrollment Germany	32 participants
Region of Enrollment Italy	92 participants
Region of Enrollment Switzerland	0 participants
Region of Enrollment United Kingdom	18 participants
Sex: Female, Male Female	29 Participants
Sex: Female, Male Male	46 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	56 / 75	41 / 69	33 / 75	30 / 55	23 / 58
other Total, other adverse events	75 / 75	68 / 69	74 / 75	38 / 55	49 / 58
serious Total, serious adverse events	39 / 75	38 / 69	39 / 75	5 / 55	10 / 58

Outcome results

None listed