Study on Tailored Treatment in Elderly Patients With Newly Diagnosed Primary Lymphoma of Central Nervous System

NCT03495960 | Completed Phase 2

• 1 other identifier: IELSG45
• Study Type: interventional
• Target: 72
• Locations: 4 countries
• Sites: 34

Brief Summary

Primary central nervous system lymphomas are rare aggressive malignancies, usually treated in two steps: an induction phase (where a combination of chemotherapy is given) followed by a consolidation phase (where patients usually receive one of the following: whole-brain irradiation, chemotherapy supported by autologous stem-cell transplantation, other type of chemotherapy, or are just observed). The feasibility of this overall strategy, for several reasons, is limited in elderly patients . This study involves patients aged ≥70 years. The more fit patients will receive the standard chemotherapy combination (high-dose methotrexate, procarbazine and rituximab) as induction. Responding patients will receive either procarbazine or lenalidomide as maintenance therapy; the aim is to evaluate the efficacy of these two drugs. The more fragile patients will receive a less aggressive therapy consisting of concomitant whole-brain radiotherapy, temozolomide and rituximab as induction therapy, followed by temozolomide as maintenance treatment; the aim is to evaluate the efficacy of this combination of treatment.

Conditions

Primary Central Nervous System Lymphoma

Keywords

non-Hodgkin's lymphoma; elderly; PCNSL

Outcome Measures

Primary Outcomes (2)

• Two years Progression Free Survival (PFS) - part A

  The primary objective is to evaluate whether lenalidomide administered as maintenance treatment after achievement of disease stabilization or better response by standard induction therapy results in a higher 2-year PFS rate as compared to procarbazine maintenance. The corresponding primary endpoint is the difference in 2-years PFS between the two treatment arms.

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years.

• Two years Progression Free Survival (PFS) - part B

  From date of maintenance start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

Secondary Outcomes (6)

• Duration of response (part A)

  From date of first assessment of response (PR or CR) until the date of first documented progression, assessed up to 2 years from randomization.

• Response Rates (part B)

  From the start of the treatment until disease progression, assessed up to 2 years from start of maintenance.

• Overall survival (OS)

  From date of induction treatment start until the date of death from any cause or the date of the last visit in patients still alive at study end, assessed up to 2 years from start of maintenance.

• Relapse rates and patterns

  From the start of the treatment until disease progression, assessed up to 2 years from start of maintenance.

• Incidence of Treatment-Emergent Adverse Events

  From the 2 weeks preceding treatment start through study completion, an average of 2.5 years

Study Arms (3)

Lenalidomide (experimental arm of part A)

EXPERIMENTAL

Patients in part A will receive 2 courses of induction chemo-immunotherapy: Rituximab 375 mg/m2 i.v. on days -6, 1, 15, 29; Methotrexate 3 g/m2 0.5 g/m2 in 15 min. +2.5 g/m2 in 3-hr inf. on days 2,16,30; Procarbazine 60 mg/m2/d oral on days 2 to 11. The duration of each treatment course is 43 days. Patients will then be randomized to receive lenalidomide or procarbazine as maintenance therapy. Lenalidomide is given 25 mg/d per os, days 1 to 21 every 4 weeks for 24 courses

Drug: Rituximab; Drug: Methotrexate; Drug: Procarbazine; Drug: Lenalidomide

Procarbazine (comparator arm of part A)

ACTIVE COMPARATOR

Patients in part A will receive 2 courses of induction chemo-immunotherapy: Rituximab 375 mg/m2 i.v. on days -6, 1, 15, 29; Methotrexate 3 g/m2 0.5 g/m2 in 15 min. +2.5 g/m2 in 3-hr inf. on days 2,16,30; Procarbazine 60 mg/m2/d oral on days 2 to 11. The duration of each treatment course is 43 days. Patients will then be randomized to receive lenalidomide or procarbazine as maintenance therapy. Procarbazine is given 100 mg/d per os, days 1 to 5 every 4 weeks for 6 courses

Drug: Rituximab; Drug: Methotrexate; Drug: Procarbazine

Radiotherapy, temozolomide and rituximab (single arm part B)

OTHER

Patients ineligible for high-dose-methotrexate will be treated in the single-arm phase II part B of the trial and will receive * whole-brain radiotherapy (2340 cGy in 5 weekly fractions) * temozolomide 75 mg/m2/d during radiotherapy * 4 weekly doses of rituximab 375 mg/m2, starting on day 2 of the whole-brain radiotherapy. Patients will then receive maintenance therapy with 12 courses of temozolomide administered on days 1-5, every 4 weeks at a dose of 150 mg/m2/d at the first course, and of 200 mg/m2/d at the subsequent courses.

Drug: Rituximab; Radiation: Radiotherapy; Drug: Temozolomide

Interventions

Rituximab DRUG

PART A - INDUCTION PHASE During the primary chemo-immunotherapy (PRIMAIN regimen, 2 courses; every 43 days) administered as induction in the PART A of the study, Rituximab is given 375 mg/m2 as standard infusion at days -6, 1, 15 \& 29. Rituximab on day -6 will be delivered only during the first course; it will be delivered between day -6 and day 0 according to clinical requirements and patient's conditions. Some patients would need for a fast chemotherapy starting. PART B - INDUCTION PHASE Patients ineligible for high-dose methotrexate, will be assigned to receive concomitant whole brain radiotherapy-temozolomide-rituximab (Induction Part B). Rituximab is given 375 mg/m2 in 4 weekly doses, starting on day 2 of radiotherapy.

Lenalidomide (experimental arm of part A); Procarbazine (comparator arm of part A); Radiotherapy, temozolomide and rituximab (single arm part B)

Methotrexate DRUG

During the primary chemo-immunotherapy (PRIMAIN regimen, 2 courses; every 43 days) administered as induction in the PART A of the study, Methotrexate is given 3 g/m2 as infusion (0.5 g/m2 in 15 min. + 2.5 g/m2 in 3-hr infusion) on days 2, 16 \& 30

Lenalidomide (experimental arm of part A); Procarbazine (comparator arm of part A)

Procarbazine DRUG

PART A - INDUCTION PHASE During the primary chemo-immunotherapy (PRIMAIN regimen, 2 courses; every 43 days) administered as induction in the PART A of the study, Procarbazine is given oral 60 mg/m2/d from days 2 to 11 PART A - MANTEINANCE PHASE (control arm) Patients responsive or with stable disease after two courses of PRIMAIN regimen (the induction treatment) will be randomly allocated to receive two different maintenance therapies. Maintenance will start on day 60 of the 2nd PRIMAIN course. Procarbazine represents the control arm and is given oral 100 mg/d from day 1 to 5 for 6 courses, every 4 weeks.

Lenalidomide (experimental arm of part A); Procarbazine (comparator arm of part A)

Lenalidomide DRUG

Patients responsive or with stable disease after two courses of PRIMAIN regimen (the induction treatment) will be randomly allocated to receive two different maintenance therapies. Maintenance will start on day 60 of the 2nd PRIMAIN course. Lenalidomide represents the experimental arm and is given oral 25 mg/d from day 1 to 21 for 24 courses; every 4 weeks.

Lenalidomide (experimental arm of part A)

Radiotherapy RADIATION

Patients ineligible for high-dose methotrexate, will be assigned to receive concomitant whole brain radiotherapy-temozolomide-rituximab (Induction Part B). Whole-brain will be irradiated by two opposite lateral fields including the first two cervical vertebras and the posterior two thirds of the eyes. Photons of 4 - 10 MeV, 180 - 200 cGy per day, 5 weekly fractions will be employed

Radiotherapy, temozolomide and rituximab (single arm part B)

Temozolomide DRUG

PART B - INDUCTION PHASE Patients ineligible for high-dose methotrexate, will be assigned to receive concomitant whole brain radiotherapy-temozolomide-rituximab (Induction Part B). Temoyolomide is given 75 mg/m2/d, every day for the whole duration of radiotherapy. PART B - MAINTENANCE PHASE Temozolomide is also given as maintenance in Part B. The treatment consists of 12 courses where temozolomide is administered on days 1-5, every 4 weeks at a dose of 150 mg/m2/d at the first course, and of 200 mg/m2/d at the subsequent courses,

Radiotherapy, temozolomide and rituximab (single arm part B)

Eligibility Criteria

• Age: 70 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• Histologically or cytologically assessed diagnosis of CD20+ diffuse large B-cell lymphoma.
• Diagnostic sample obtained by stereotactic or surgical biopsy, CSF cytology examination or vitrectomy.
• Lymphoma exclusively localized in the central nervous system (brain parenchyma and/or meningeal/CSF dissemination and/or eyes and/or cranial nerves).
• Previously untreated patients (previous or ongoing steroid therapy admitted).
• Age ≥70 years
• Patients not eligible for high-dose chemotherapy supported by autologous stem cell transplant
• ECOG PS ≤3.
• Adequate bone marrow, cardiac, renal, and hepatic function
• No 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 for 3 years (patients with a previous lymphoma at any time are NOT eligible).
• Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• No concurrent treatment with other experimental drugs.
• Patients receiving oral lenalidomide or procarbazine must agree to avoid sharing the study medication with another person and to return all unused study drug to the investigator.
• Male patients must agree to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide, during dose interruptions and for up to 7 days after treatment discontinuation, even if they have undergone a successful vasectomy.
• Informed consent from the patient, or legal representative, obtained before registration.

You may not qualify if:

• Lymphoma entity other than diffuse large B-cell lymphoma.
• Extra-CNS disease.
• Lymphoma exclusively localized in the eyes
• Lymphoma infiltration of the cranial nerves as exclusive site of disease
• Previous antineoplastic treatment for the PCNSL.
• Patients eligible for ASCT.
• HIV disease or immunodeficiency.
• Severe concomitant illnesses/medical conditions (e.g. impaired respiratory and/or cardiac function, uncontrolled diabetes mellitus despite optimal medical management).
• Active infectious disease.
• Hypersensitivity to any active principle and/or any excipient according to the contraindications reported in the Summary of Product Characteristics (SmPCs) of the anticancer drugs used in the study

Sponsors & Collaborators

• International Extranodal Lymphoma Study Group (IELSG): lead

Study Sites (34)

Aarhus University Hospital

Aarhus, Denmark

Location

Odense University Hospital

Odense, Denmark

Location

Oulu University Hospital

Oulu, Finland

Location

Tampere University Hospital

Tampere, Finland

Location

Centro di Riferimento Oncologico

Aviano, (PN), 33081, Italy

Location

Ospedale C.e G. Mazzoni

Ascoli Piceno, Italy

Location

Bari IRCCS Istituto Tumori

Bari, Italy

Location

ASST Spedali Civili di Brescia

Brescia, Italy

Location

Ospedale Antonio Perrino

Brindisi, Italy

Location

Azienda Ospedaliera Universitaria (AOU) Careggi

Florence, Italy

Location

Meldola, IRST - ISTITUTO SCIENTIFICO ROMAGNOLO PER LO STUDIO E LA CURA DEI TUMORI

Meldola, Italy

Location

Milano, IRCCS Ospedale San Raffaele

Milan, 20132, Italy

Location

Milano - Îstituto Besta

Milan, Italy

Location

Milano Niguarda

Milan, Italy

Location

Modena, Policlinico Universitario

Modena, Italy

Location

ASST Monza - Ospedale S. Gerardo

Monza, Italy

Location

Pescara, Presidio Ospedaliero UOS dipartimentale centro di diagnosi e terapia Linfomi

Pescara, Italy

Location

Piacenza

Piacenza, Italy

Location

Ravenna - Ospedale di Ravenna - IRST

Ravenna, Italy

Location

Reggio Emilia - Arcispedale Santa Maria Nuova - IRCCS

Reggio Emilia, Italy

Location

AUSL della Romagna - Presidio Ospedaliero Rimini - Ospedale "Infermi"

Rimini, Italy

Location

Policlinico Umberto I - Università La Sapienza

Roma, Italy

Location

Roma - Unicampus-Bio

Roma, Italy

Location

S. Giovanni Rotondo - Casa Sollievo della sofferenza

San Giovanni Rotondo, Italy

Location

Siena - Azienda Ospedaliera Universitaria Senese

Siena, Italy

Location

Terni - Ospedale di Terni

Terni, Italy

Location

Torino neurooncologia - AOU CITTA' DELLA SALUTE E DELLA SCIENZA DI TORINO

Torino, Italy

Location

Tricase - Ospedale "Card. G. Panico"

Tricase, Italy

Location

Udine, Azienda Ospedaliera Universitaria

Udine, Italy

Location

Basel - Universitätsspital

Basel, Switzerland

Location

IOSI - Oncology Institute of Southern Switzerland

Bellinzona, 6500, Switzerland

Location

Bern - Inselspital

Bern, Switzerland

Location

St. Gallen - Kantonsspital

Sankt Gallen, Switzerland

Location

Universitätsspital Zürich

Zurich, CH-8091, Switzerland

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

Rituximab; Methotrexate; Procarbazine; Lenalidomide; Radiotherapy; Temozolomide

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phthalimides; Phthalic Acids; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Isoindoles; Therapeutics; Dacarbazine; Triazenes; Imidazoles; Azoles

Study Officials

• Andrès JM Ferreri, MD

  IRCCS San Raffaele Scientific Institute, Milan, Italy

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicenter open label phase II trial. The patients will be stratified according to their suitability to tolerate an induction chemo-immunotherapy regimen containing high-dose methotrexate. Patients eligible for high-dose methotrexate-based induction chemotherapy will enter the run-in phase of Part A of the study and after the induction phase will be randomly assigned to procarbazine or lenalidomide maintenance monotherapy. Forty assessable patients per treatment arm are required. Patients ineligible for high-dose methotrexate-based induction chemotherapy will be treated în Part B with concomitant whole-brain radiotherapy, temozolomide and rituximab and will receive temozolomide as maintenance.According to the Simon's two-stage minimax design, 46 patients will be treated in the first stage. If ≤ 16 patients will be progression-free at 2 years from maintenance treatment start, the study will be stopped. Otherwise, 19 additional patients will be treated for a total of 65

Study Record Dates

• First Submitted: March 23, 2018
• First Posted: April 12, 2018
• Study Start: June 15, 2019
• Primary Completion: December 12, 2024
• Study Completion: December 12, 2024
• Last Updated: January 30, 2025

Record last verified: 2025-01

Locations

IT (25); FI (2); DK (2); CH (5)