Clinical trial NCT02710643: "MIRO" Molecularly Oriented Immuno-radio-therapy
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Follicular Lymphoma, Grade 1
Follicular Lymphoma, Grade 2
Follicular Lymphoma Grade 3A
Keywords: Follicular
Lymphoma
Grade 1
Grade 2
Grade 3A
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
First posted: 2016-03-17
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility 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.

Primary outcomes:
measure: Bcl-2 negativization after Ofatumumab
timeFrame: 4 YEARS FROM ENROLLMENT
Secondary outcomes:
measure: Clinical response rate
timeFrame: 4 YEARS FROM ENROLLMENT
measure: Overall response
timeFrame: 4 YEARS FROM ENROLLMENT
measure: Partial response
timeFrame: 4 YEARS FROM ENROLLMENT
measure: Complete response
timeFrame: 4 YEARS FROM ENROLLMENT
measure: Progression Free Survival
timeFrame: 4 YEARS FROM ENROLLMENT
measure: Relapse Free Survival
timeFrame: 4 YEARS FROM ENROLLMENT
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: Ospedale SS. Antonio e Biagio e Cesare Arrigo
state: AL
city: Bari
country: Italy
facility: Ematologia Azienda Ospedaliera Policlinico
state: BA
city: Brescia
country: Italy
facility: A.O. Spedali Civili
state: BS
city: Milano
country: Italy
facility: A.O. Niguarda
state: MI
city: Monza
country: Italy
facility: Azienda Ospedaliera S. Gerardo Di Monza
state: Monza Brianza
city: Ravenna
country: Italy
facility: Osp. S. Maria delle Croci
state: RA
city: Reggio Calabria
country: Italy
facility: A.O. Bianchi - Melacrino - Morelli
state: RC
city: Latina
country: Italy
facility: Polo Pontino
state: Roma
city: Matera
country: Italy
facility: Ospedale di Matera
city: Meldola (FC)
country: Italy
facility: Area Vasta Romagna e IRST
city: Messina
country: Italy
facility: Ospedali Riuniti Papardo
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
city: Milano
country: Italy
facility: Ospedale S. Raffaele
city: Novara
country: Italy
facility: S.C.D.U Ematologia Azienda Ospedaliero Universitaria Maggiore
city: Parma
country: Italy
facility: U.O. Complessa di Ematologia Ospedale di Parma
city: Pavia
country: Italy
facility: IRCCS Policlinico S. Matteo di Pavia
city: Piacenza
country: Italy
facility: Ausl Di Piacenza
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana U.O. Ematologia
city: Reggio Emilia
country: Italy
facility: AO Santa Maria Nuova
city: Rimini
country: Italy
facility: Ausl Di Rimini
city: Roma
country: Italy
facility: Ematologia e Trapianto Istituto Regina Elena IFO
city: Roma
country: Italy
facility: Policlinico Umberto I - Università "La Sapienza" - Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia
city: Sassuolo (MO)
country: Italy
facility: Ospedale civile DH oncologico
city: Siena
country: Italy
facility: Policlinico Le Scotte Clinica Ematologica
city: Terni
country: Italy
facility: SC Oncoematologia con autotrapianto AO Santa Maria
city: Torino
country: Italy
facility: A.O. Universitaria Citta' Della Salute E Della Scienza Di Torino
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza di Torino
Study officials:
affiliation: Policlinico Umberto I - Università "La Sapienza" - Istituto Ematologia
name: Alessandro Pulsoni, MD
role: STUDY_CHAIR
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