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"MIRO" Molecularly Oriented Immuno-radio-therapy (FIL_MIRO)

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ClinicalTrials.gov Identifier: NCT02710643
Recruitment Status : Active, not recruiting
First Posted : March 17, 2016
Last Update Posted : November 21, 2018
Sponsor:
Information provided by (Responsible Party):
Fondazione Italiana Linfomi ONLUS

Brief Summary:

Phase II prospective multicenter study for stage I/II Follicular Lymphoma treated with involved-field radiotherapy (IFRT) at doses of 24 Gy) with or without Ofatumumab for 8 weekly doses on molecular basis. Patients with positive basal Bcl-2 will be followed every 3 months and with Bcl-2 detection every 6 months for 3 years. Patient with negative basal Bcl-2 will be followed every 3 months without further Bcl-2 detection.

Ofatumumab treatment will be administered to:

  1. Patients with positive basal PCR for Bcl-2-IgH rearrangement in BM and/or PB, resulting still positive after IFRT;
  2. Patients with positive basal PCR for Bcl-2-IgH in

Condition or disease Intervention/treatment Phase
Follicular Lymphoma, Grade 1 Follicular Lymphoma, Grade 2 Follicular Lymphoma Grade 3A Drug: OFATUMUMAB Phase 2

Detailed Description:

Stage I/IIA follicular lymphoma (FL) is considered a localized disease that can be adequately treated with radiotherapy alone. This strategy is recommended by the guidelines of the "Società Italiana di Ematologia" (SIE) and of the "European Society for Medical Oncology" (ESMO) The accurate definition of the truly localised forms represents a crucial issue in order to ensure an appropriate treatment design for such patients. The characteristic t(14;18) translocation, which leads to the over-expression of the Bcl-2 gene, is found in approximately 85% of FL; cells bearing this translocation can be detected in the peripheral blood (PB) or bone marrow (BM) by polymerase chain reaction (PCR).

PCR for the t(14;18) translocation provides a sensitive device to identify the presence of minimal non-Hodgkin lymphoma (NHL) cell contamination. Previous experiences have demonstrated that despite the limited stage, Bcl-2/IgH+ cells can be found at diagnosis in PB and/or BM of the majority of the patients. After treatment with local radiotherapy confined to the involved lymph node(s) only, disappearance of circulating Bcl-2/IgH+ cells in PB and/or BM was demonstrated in approximately 60% of positive patients. Quantitative PCR demonstrated the feasibility of clearing PB and BM Bcl-2+ cells after local irradiation of the primary site of the disease only when the basal number of lymphoma cells was <1:100 000.

Anti-CD20 monoclonal antibody treatment has clearly demonstrated, both alone and in combination with chemotherapy and radiotherapy, a high therapeutic potential in FL. A significant impact of treatment with the anti CD20 monoclonal antibody in reducing the minimal residual disease in FL has been demonstrated in several studies when used as consolidation or during the maintenance phase.

No data are currently available concerning the ability of anti-CD20 antibody treatment in reducing the proportion of Bcl-2 positive residual cells after radiotherapy in localized FL. The objective of this study is to take advantage of the therapeutic potential of anti-CD20 monoclonal antibody to reduce or eliminate minimal residual disease in patients with FL in localized stage (I/II) after conventional treatment with local radiotherapy of the involved site(s). The effectiveness of anti-CD20 monoclonal antibody treatment will be determined by the proportion of negativization of residual Bcl-2 positive cells after radiotherapy, evaluated by qualitative and quantitative PCR detection of viable Bcl-2/IgH rearranged cells in PB and/or BM.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: "MIRO" (Molecularly Oriented Immuno - Radio -Therapy): Multicenter Phase II Study for the Treatment of the Molecular Basis of Stage I / II Follicular Lymphoma With Local Radiotherapy With / Without Ofatumumab
Study Start Date : October 2014
Actual Primary Completion Date : April 2018
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Ofatumumab

Arm Intervention/treatment
No Intervention: MRD - BEFORE RT
Patients who had negative baseline Bcl-2 in PB and BM will not undergo further treatment after radiotherapy; they will not repeat Bcl-2 during subsequent follow-up visits.
No Intervention: MRD + BEFORE RT AND MRD - AFTER RT
Patients who had positive baseline Bcl-2 in PB and / or BM and become negative after local radiotherapy will not undergo further treatment.
Experimental: MRD + BEFORE RT AND MRD + AFTER RT

Patients who had positive baseline Bcl-2 in PB and / or BM and remain positive after local radiotherapy get Ofatumumab (8 weekly infusion of 1000 mg total dose).

Patients Bcl-2 negativized either after radiotherapy or after Ofatumumab, who became Bcl-2 positive during the follow-up monitoring will be treated/retreated with Ofatumumab 8 weekly infusions at the conventional dose of 1000 mg; Bcl-2 monitoring will be continued subsequently according to the program.In case of persistent positive PCR after Ofatumumab the treatment will not be repeated.

Drug: OFATUMUMAB
8 weekly infusion of 1000 mg total dose
Other Name: ARZERRA




Primary Outcome Measures :
  1. Bcl-2 negativization after Ofatumumab [ Time Frame: 4 YEARS FROM ENROLLMENT ]
    The proportion of Bcl-2 negativization after Ofatumumab treatment will be estimated by the proportion, and its confidence interval, of residual Bcl-2 positive cases after radiotherapy, which will became negative after Ofatumumab treatment


Secondary Outcome Measures :
  1. Clinical response rate [ Time Frame: 4 YEARS FROM ENROLLMENT ]
    Clinical response rate will be evaluated by the proportion and its confidence interval of patients achieving overall response (OR) complete response (CR) and partial response (PR).

  2. Overall response [ Time Frame: 4 YEARS FROM ENROLLMENT ]
    overall response (OR)

  3. Partial response [ Time Frame: 4 YEARS FROM ENROLLMENT ]
    partial response (PR)

  4. Complete response [ Time Frame: 4 YEARS FROM ENROLLMENT ]
    complete response (CR)

  5. Progression Free Survival [ Time Frame: 4 YEARS FROM ENROLLMENT ]
    Progression Free Survival (PFS) is defined as the length of time between the date of registration and the earliest date of disease progression or death due to any cause; If the patients doesn't not have a documented date of progression or death, the PFS will be censored at the date of last adequate assessment. Relapse Free Survival (RFS) is defined as the length of time between the achievement of Complete Remission (CR) and Relapse of disease

  6. Relapse Free Survival [ Time Frame: 4 YEARS FROM ENROLLMENT ]
    Relapse Free Survival (RFS) is defined as the length of time between the achievement of Complete Remission (CR) and Relapse of disease



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed follicular lymphoma grade I-IIIa;
  • Stage IA or IIA (no more than 2 contiguous nodal regions) non bulky (<7 cm);
  • FLIPI ≤2, FLIPI2 ≤2;
  • Previously untreated;
  • Age ≥ 18;
  • Informed consent;
  • Staging with PET-CT, bone marrow biopsy;
  • Qualitative/quantitative PCR basal evaluation of Bcl-2/IgH rearranged cells in peripheral blood and bone marrow.

Exclusion Criteria:

  • Follicular lymphoma grade IIIb;
  • Stage greater than II with more than 2 nodal sites and/or B symptoms and/or bulky disease (>7 cm);
  • FLIPI >2, FLIPI2 >2;
  • Age < 18;
  • Previous treatments for non-Hodgkin's lymphoma;
  • Dementia;
  • Impossibility to subscribe the informed consent;
  • Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones or stable chronic liver disease per investigator assessment);
  • Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study;
  • Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible;
  • Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C;
  • History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae;
  • Known HIV positive;
  • Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to start of treatment, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities;
  • Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient;
  • Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a quantitative HBV-DNA test will be performed and if positive the subject will be excluded. Patients with HBcAb positivity and negative HBV DNA should be prophilactically treated with oral Lamivudine (100 mg /day) in case of treatment with Ofatumumab, to be prosecuted 12 months after treatment;
  • Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HCV-RNA on the same sample to confirm the result;
  • Hematologic and blood chemistry exclusion criteria:

    • platelets <50 x 109/L;
    • neutrophils <1.0 x 109/L;
    • creatinine >2.0 times upper normal limit;
    • total bilirubin >1.5 times upper normal limit;
    • ALT >2.5 times upper normal limit;
    • alkaline phosphatase >2.5 times upper normal limit;
  • Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening:

    - Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence;

  • Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

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): NCT02710643


Locations
Italy
Ospedale SS. Antonio e Biagio e Cesare Arrigo
Alessandria, AL, Italy, 15121
Ematologia Azienda Ospedaliera Policlinico
Bari, BA, Italy
Azienda Ospedaliera Caravaggio
Treviglio, Bergamo, Italy, 24127
A.O. Spedali Civili
Brescia, BS, Italy, 25100
IRCCS Casa Sollievo Della Sofferenza
San Giovanni Rotondo (FG), FG, Italy, 71013
IRCCS San Martino - IST
Genova, GE, Italy, 16132
A.O. Niguarda
Milano, MI, Italy, 20162
Azienda Ospedaliera S. Gerardo Di Monza
Monza, Monza Brianza, Italy, 20900
Osp. S. Maria delle Croci
Ravenna, RA, Italy, 48121
A.O. Bianchi - Melacrino - Morelli
Reggio Calabria, RC, Italy, 89125
Polo Pontino
Latina, Roma, Italy, 04100
Ospedale S. Luigi Gonzaga,
Orbassano, TO, Italy, 10043
Ospedale Mauriziano
Torino, TO, Italy, 10128
Ospedale Civile di Mirano
Mirano, VE, Italy, 30035
ULSS5 UOC Medicina Generale Ospedale Valdagno
Valdagno, Vicenza, Italy
Centro di riferimento Oncologico Oncologia Medica A
Aviano (Pordenone), Italy
Ospedale della Versilia USL12 - UOC Medicina - Sezione Ematologia
Camaiore, Italy
A.O. Universitaria Ospedale Vittorio Emanuele E Ferrarotto Di Catania
Catania, Italy, 95124
UO Ematologia PO Vito Fazzi
Lecce, Italy
Ospedale di Matera
Matera, Italy, 75100
Area Vasta Romagna e IRST
Meldola (FC), Italy
Ospedali Riuniti Papardo
Messina, Italy, 98158
Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
Milano, Italy, 120133
Ospedale S. Raffaele
Milano, Italy, 20132
Istituto Europeo Oncologico
Milano, Italy
Ospedale Maggiore IRCCS-Dipartimento di Ematologia
Milano, Italy
Ospedale San Gennaro
Napoli, Italy
S.C.D.U Ematologia Azienda Ospedaliero Universitaria Maggiore
Novara, Italy
U.O. Complessa di Ematologia Ospedale di Parma
Parma, Italy, 43100
IRCCS Policlinico S. Matteo di Pavia
Pavia, Italy, 27100
Azienda Ospedaliera Di Perugia - Ospedale S. Maria Della Misericordia -
Perugia, Italy, 06134
Ematologia e Centro Trapianti
Pesaro, Italy
Ausl Di Piacenza
Piacenza, Italy, 29121
Azienda Ospedaliero Universitaria Pisana U.O. Ematologia
Pisa, Italy
AO Santa Maria Nuova
Reggio Emilia, Italy, 42123
Ausl Di Rimini
Rimini, Italy, 47924
Ematologia Ospedale S.Camillo Forlanini
Roma, Italy, 00149
Ematologia e Trapianto Istituto Regina Elena IFO
Roma, Italy
Policlinico Umberto I - Università "La Sapienza" - Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia
Roma, Italy
Ospedale civile DH oncologico
Sassuolo (MO), Italy
Policlinico Le Scotte Clinica Ematologica
Siena, Italy
SC Oncoematologia con autotrapianto AO Santa Maria
Terni, Italy, 05100
A.O. Universitaria Citta' Della Salute E Della Scienza Di Torino
Torino, Italy, 10126
A.O.U. Citta della Salute e della Scienza di Torino
Torino, Italy, 10126
Sponsors and Collaborators
Fondazione Italiana Linfomi ONLUS
Investigators
Study Chair: Alessandro Pulsoni, MD Policlinico Umberto I - Università "La Sapienza" - Istituto Ematologia

Publications:

Responsible Party: Fondazione Italiana Linfomi ONLUS
ClinicalTrials.gov Identifier: NCT02710643     History of Changes
Other Study ID Numbers: FIL_MIRO
First Posted: March 17, 2016    Key Record Dates
Last Update Posted: November 21, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Final study report

Keywords provided by Fondazione Italiana Linfomi ONLUS:
Follicular
Lymphoma
Grade 1
Grade 2
Grade 3A

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Ofatumumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs