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

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ClinicalTrials.gov Identifier: NCT03495960
Recruitment Status : Recruiting
First Posted : April 12, 2018
Last Update Posted : November 13, 2019
Sponsor:
Information provided by (Responsible Party):
International Extranodal Lymphoma Study Group (IELSG)

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.


Condition or disease Intervention/treatment Phase
Primary Central Nervous System Lymphoma Drug: Rituximab Drug: Methotrexate Drug: Procarbazine Drug: Lenalidomide Radiation: Radiotherapy Drug: Temozolomide Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 208 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial on Fitness- and Comorbidity- Tailored Treatment in Elderly Patients With Newly Diagnosed Primary CNS Lymphoma (FIORELLA Trial)
Actual Study Start Date : June 15, 2019
Estimated Primary Completion Date : October 31, 2023
Estimated Study Completion Date : October 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Lenalidomide (experimental arm of part A)

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

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.


Drug: Methotrexate
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

Drug: Procarbazine

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.


Drug: Lenalidomide

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.


Active Comparator: Procarbazine (comparator arm of part A)

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

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.


Drug: Methotrexate
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

Drug: Procarbazine

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.


Radiotherapy, temozolomide and rituximab (single arm part B)

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

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.


Radiation: Radiotherapy
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

Drug: Temozolomide

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,





Primary Outcome Measures :
  1. Two years Progression Free Survival (PFS) - part A [ Time Frame: 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. ]

    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.


  2. Two years Progression Free Survival (PFS) - part B [ Time Frame: 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 Outcome Measures :
  1. Duration of response (part A) [ Time Frame: From date of first assessment of response (PR or CR) until the date of first documented progression, assessed up to 2 years from randomization. ]
    Difference between the two arms in time from first assessment of response (PR or CR) to relapse/progression

  2. Response Rates (part B) [ Time Frame: From the start of the treatment until disease progression, assessed up to 2 years from start of maintenance. ]
    Proportion of patients showing CR, PR, SD, PD as best response to treatment

  3. Overall survival (OS) [ Time Frame: 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. ]
  4. Relapse rates and patterns [ Time Frame: From the start of the treatment until disease progression, assessed up to 2 years from start of maintenance. ]
    Analysis of the following relapse rates and patterns: primary site vs. secondary CNS sites vs. extra-CNS sites; CNS sites: brain, meninges, cranial nerves, and/or eyes

  5. Incidence of Treatment-Emergent Adverse Events [ Time Frame: From the 2 weeks preceding treatment start through study completion, an average of 2.5 years ]
    Analysis of adverse events and adverse reactions incidence and severity

  6. Early and late neurotoxicity [ Time Frame: From maintenance up to 2 years. ]
    Analysis of incidence and severity of early and late neurotoxicity assessed by specific neuropsychological and quality of life tests up to 2 years from maintenance treatment start



Information from the National Library of Medicine

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Ages Eligible for Study:   70 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  • HBsAg- and HCV-positive patients; HBsAg- and HCV-positive patients. HBcAb+ is not exclusion criteria in the absence of detectable levels HBVDNA.
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03495960


Contacts
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Contact: Emanuele Zucca, MD +41 91 811 9040 ielsg@eoc.ch

Locations
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Italy
Bari IRCCS Istituto Tumori Recruiting
Bari, Italy
Contact: Attilio Guarini         
Principal Investigator: Attilio Guarini         
Meldola, IRST - ISTITUTO SCIENTIFICO ROMAGNOLO PER LO STUDIO E LA CURA DEI TUMORI Not yet recruiting
Meldola, Italy
Contact: , MD         
Principal Investigator: Gerardo Musuraca, MD         
Milano, IRCCS Ospedale San Raffaele Recruiting
Milan, Italy, 20132
Contact: Andrès Ferreri, MD         
Principal Investigator: Andrès Ferreri, MD         
Milano - Îstituto Besta Recruiting
Milan, Italy
Principal Investigator: Antonio Silvani, MD         
Milano Niguarda Recruiting
Milan, Italy
Principal Investigator: Chiara Rusconi, MD         
Modena, Policlinico Universitario Recruiting
Modena, Italy
Principal Investigator: Fabio Forghieri, MD         
Padova, Istituto Oncologico Veneto Not yet recruiting
Padova, Italy
Principal Investigator: Dario Marino, MD         
Parma, Azienda Ospedaliera Not yet recruiting
Parma, Italy
Principal Investigator: Francesca Re, MD         
Pescara, Presidio Ospedaliero UOS dipartimentale centro di diagnosi e terapia Linfomi Not yet recruiting
Pescara, Italy
Principal Investigator: Francesco Angrilli, MD         
Piacenza Not yet recruiting
Piacenza, Italy
Principal Investigator: Annalisa Arcari, MD         
Ravenna - Ospedale di Ravenna - IRST Not yet recruiting
Ravenna, Italy
Principal Investigator: Monica Tani, MD         
Reggio Emilia - Arcispedale Santa Maria Nuova - IRCCS Recruiting
Reggio Emilia, Italy
Principal Investigator: Fiorella Ilariucci, MD         
Roma - Ospedale S. Andrea Not yet recruiting
Roma, Italy
Principal Investigator: Agostino Tafuri, MD         
Roma - Unicampus-Bio Recruiting
Roma, Italy
Principal Investigator: Ombretta Annibali, MD         
S. Giovanni Rotondo - Casa Sollievo della sofferenza Recruiting
San Giovanni Rotondo, Italy
Principal Investigator: Nicola Cascavilla, MD         
Siena - Azienda Ospedaliera Universitaria Senese Not yet recruiting
Siena, Italy
Principal Investigator: Alberto Fabbri, MD         
Terni - Ospedale di Terni Not yet recruiting
Terni, Italy
Principal Investigator: Anna M Liberati, MD         
Torino neurooncologia - AOU CITTA' DELLA SALUTE E DELLA SCIENZA DI TORINO Recruiting
Torino, Italy
Principal Investigator: Roberta Rudà, MD         
Tricase - Ospedale "Card. G. Panico" Not yet recruiting
Tricase, Italy
Principal Investigator: Vincenzo Pavone, MD         
Udine, Azienda Ospedaliera Universitaria Recruiting
Udine, Italy
Contact: Francesco Zaja         
Principal Investigator: Francesco Zaja         
Switzerland
Basel - Universitätsspital Recruiting
Basel, Switzerland
Contact: Benjamin kasenda, MD         
Principal Investigator: Benjamin Kasenda         
IOSI - Oncology Institute of Southern Switzerland Recruiting
Bellinzona, Switzerland, 6500
Principal Investigator: Emanuele Zucca, MD         
Bern - Inselspital Recruiting
Bern, Switzerland
Principal Investigator: Urban Novak, MD         
Lausanne - CHUV Not yet recruiting
Lausanne, Switzerland
Principal Investigator: Anne Cairoli, MD         
St. Gallen - Kantonsspital Recruiting
Saint Gallen, Switzerland
Principal Investigator: Felicitas Hitz, MD         
Sponsors and Collaborators
International Extranodal Lymphoma Study Group (IELSG)
Investigators
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Study Chair: Andrès JM Ferreri, MD IRCCS San Raffaele Scientific Institute, Milan, Italy

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Responsible Party: International Extranodal Lymphoma Study Group (IELSG)
ClinicalTrials.gov Identifier: NCT03495960     History of Changes
Other Study ID Numbers: IELSG45
First Posted: April 12, 2018    Key Record Dates
Last Update Posted: November 13, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by International Extranodal Lymphoma Study Group (IELSG):
non-Hodgkin's lymphoma
elderly
PCNSL
Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Methotrexate
Lenalidomide
Temozolomide
Procarbazine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Nucleic Acid Synthesis Inhibitors
Angiogenesis Inhibitors
Angiogenesis Modulating Agents