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Follicular Lymphoma, Grade 1Phase 2FIL_MIRONCT02710643

"MIRO" Molecularly Oriented Immuno-radio-therapy

A Phase 2 study testing OFATUMUMAB in people with Follicular Lymphoma, Grade 1 and Follicular Lymphoma, Grade 2, run by Fondazione Italiana Linfomi - ETS at 27 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
OFATUMUMAB
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
110 participants
Where
27 sitesItaly
Study dates
Oct 2014to 7 Apr 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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;
Show all 27Show fewer
  • 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.

Trial locations and contacts

27 sites in 1 country.

27 sites in 1 country

Italy27 sites

  • Ospedale SS. Antonio e Biagio e Cesare Arrigo

    Alessandria, AL, 15121

  • Ematologia Azienda Ospedaliera Policlinico

    Bari, BA

  • A.O. Spedali Civili

    Brescia, BS, 25100

  • Polo Pontino

    Latina, Roma, 04100

  • Ospedale di Matera

    Matera, 75100

  • Area Vasta Romagna e IRST

    Meldola (FC)

  • Ospedali Riuniti Papardo

    Messina, 98158

  • A.O. Niguarda

    Milan, MI, 20162

  • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

    Milan, 120133

  • Ospedale S. Raffaele

    Milan, 20132

  • Azienda Ospedaliera S. Gerardo Di Monza

    Monza, Monza Brianza, 20900

  • S.C.D.U Ematologia Azienda Ospedaliero Universitaria Maggiore

    Novara

  • U.O. Complessa di Ematologia Ospedale di Parma

    Parma, 43100

  • IRCCS Policlinico S. Matteo di Pavia

    Pavia, 27100

  • Ausl Di Piacenza

    Piacenza, 29121

  • Azienda Ospedaliero Universitaria Pisana U.O. Ematologia

    Pisa

  • Osp. S. Maria delle Croci

    Ravenna, RA, 48121

  • A.O. Bianchi - Melacrino - Morelli

    Reggio Calabria, RC, 89125

  • AO Santa Maria Nuova

    Reggio Emilia, 42123

  • Ausl Di Rimini

    Rimini, 47924

  • Ematologia e Trapianto Istituto Regina Elena IFO

    Roma

  • Policlinico Umberto I - Università "La Sapienza" - Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia

    Roma

  • Ospedale civile DH oncologico

    Sassuolo (MO)

  • Policlinico Le Scotte Clinica Ematologica

    Siena

  • SC Oncoematologia con autotrapianto AO Santa Maria

    Terni, 05100

  • A.O. Universitaria Citta' Della Salute E Della Scienza Di Torino

    Torino, 10126

  • A.O.U. Citta della Salute e della Scienza di Torino

    Torino, 10126

Other trials in Italy

About this study

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

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
Read the 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.

Being tested
OFATUMUMAB
Keywords
Follicular, Lymphoma, Grade 1, Grade 2, Grade 3A
Medical subject headings
Lymphoma, Follicular, Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • OFATUMUMABDrug

    Also called ARZERRA

    8 weekly infusion of 1000 mg total dose

Study groups in NCT02710643
Study groupRoleWhat they receive
MRD - BEFORE RTNo interventionPatients 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.
MRD + BEFORE RT AND MRD - AFTER RTNo interventionPatients who had positive baseline Bcl-2 in PB and / or BM and become negative after local radiotherapy will not undergo further treatment.
MRD + BEFORE RT AND MRD + AFTER RTExperimentalPatients 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.
Receives: Drug: OFATUMUMAB

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Bcl-2 negativization after Ofatumumab

    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

    Measured: 4 YEARS FROM ENROLLMENT

Secondary outcomes (6)

  1. Clinical response rate

    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).

    Measured: 4 YEARS FROM ENROLLMENT

  2. Overall response

    overall response (OR)

    Measured: 4 YEARS FROM ENROLLMENT

  3. Partial response

    partial response (PR)

    Measured: 4 YEARS FROM ENROLLMENT

  4. Complete response

    complete response (CR)

    Measured: 4 YEARS FROM ENROLLMENT

  5. Progression Free Survival

    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

    Measured: 4 YEARS FROM ENROLLMENT

  6. Relapse Free Survival

    Relapse Free Survival (RFS) is defined as the length of time between the achievement of Complete Remission (CR) and Relapse of disease

    Measured: 4 YEARS FROM ENROLLMENT

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Mar 2016 (estimated)
  2. Study startOct 2014
  3. Primary completionApr 2018
  4. Study completion7 Apr 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
110 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02710643
Sponsor's protocol ID
FIL_MIRO
Acronym
FIL_MIRO
Status last verified
Jun 2022
First submitted
26 Feb 2016
Last updated
21 Jun 2022
Results posted
No
Data monitoring committee
No
Individual data sharing
Yes: Final study report

Publications

  • Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. doi: 10.1093/jnci/85.5.365.

    PubMed 8433390

  • Abbott BL. Chronic lymphocytic leukemia: recent advances in diagnosis and treatment. Oncologist. 2006 Jan;11(1):21-30. doi: 10.1634/theoncologist.11-1-21.

    PubMed 16401710

  • Apostolidis J, Gupta RK, Grenzelias D, Johnson PW, Pappa VI, Summers KE, Salam A, Adams K, Norton AJ, Amess JA, Matthews J, Bradburn M, Lister TA, Rohatiner AZ. High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up. J Clin Oncol. 2000 Feb;18(3):527-36. doi: 10.1200/JCO.2000.18.3.527.

    PubMed 10653868

  • Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol. 1998 Aug;16(8):2780-95. doi: 10.1200/JCO.1998.16.8.2780.

    PubMed 9704731

  • Barosi G, Carella A, Lazzarino M, Marchetti M, Martelli M, Rambaldi A, Tarella C, Vitolo U, Zinzani PL, Tura S. Management of nodal indolent (non marginal-zone) non-Hodgkin's lymphomas: practice guidelines from the Italian Society of Hematology, Italian Society of Experimental Hematology and Italian Group for Bone Marrow Transplantation. Haematologica. 2005 Sep;90(9):1236-57.

    PubMed 16154848

  • Berinstein NL, Reis MD, Ngan BY, Sawka CA, Jamal HH, Kuzniar B. Detection of occult lymphoma in the peripheral blood and bone marrow of patients with untreated early-stage and advanced-stage follicular lymphoma. J Clin Oncol. 1993 Jul;11(7):1344-52. doi: 10.1200/JCO.1993.11.7.1344.

    PubMed 8315432

  • Binet JL, Caligaris-Cappio F, Catovsky D, Cheson B, Davis T, Dighiero G, Dohner H, Hallek M, Hillmen P, Keating M, Montserrat E, Kipps TJ, Rai K; International Workshop on Chronic Lymphocytic Leukemia (IWCLL). Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood. 2006 Feb 1;107(3):859-61. doi: 10.1182/blood-2005-04-1677. Epub 2005 Oct 13.

    PubMed 16223776

  • Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198-206. doi: 10.1002/1097-0142(19810701)48:13.0.co;2-v.

    PubMed 7237385

  • Weiss LM, Warnke RA, Sklar J, Cleary ML. Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med. 1987 Nov 5;317(19):1185-9. doi: 10.1056/NEJM198711053171904.

    PubMed 3657890

  • Brown JR, Feng Y, Gribben JG, Neuberg D, Fisher DC, Mauch P, Nadler LM, Freedman AS. Long-term survival after autologous bone marrow transplantation for follicular lymphoma in first remission. Biol Blood Marrow Transplant. 2007 Sep;13(9):1057-65. doi: 10.1016/j.bbmt.2007.05.012. Epub 2007 Jul 16.

    PubMed 17697968

  • Ygge J. [Acute heparin therapy--standard dose or dosage according to individual sensitivity?]. Lakartidningen. 1977 Mar 9;74(10):921-4. No abstract available. Swedish.

    PubMed 839876

  • Gribben JG, Freedman AS, Neuberg D, Roy DC, Blake KW, Woo SD, Grossbard ML, Rabinowe SN, Coral F, Freeman GJ, et al. Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med. 1991 Nov 28;325(22):1525-33. doi: 10.1056/NEJM199111283252201.

    PubMed 1944436

  • Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395-419. doi: 10.1146/annurev.immunol.16.1.395.

    PubMed 9597135

  • Corradini P, Ladetto M, Zallio F, Astolfi M, Rizzo E, Sametti S, Cuttica A, Rosato R, Farina L, Boccadoro M, Benedetti F, Pileri A, Tarella C. Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes. J Clin Oncol. 2004 Apr 15;22(8):1460-8. doi: 10.1200/JCO.2004.10.054.

    PubMed 15084619

  • Lopez-Guillermo A, Cabanillas F, McDonnell TI, McLaughlin P, Smith T, Pugh W, Hagemeister F, Rodriguez MA, Romaguera JE, Younes A, Sarris AH, Preti HA, Lee MS. Correlation of bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma. Blood. 1999 May 1;93(9):3081-7.

    PubMed 10216105

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing OFATUMUMAB in people with Follicular Lymphoma, Grade 1 and Follicular Lymphoma, Grade 2, run by Fondazione Italiana Linfomi - ETS at 27 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 27 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Bcl-2 negativization after Ofatumumab (time frame: 4 YEARS FROM ENROLLMENT). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02710643, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jun 2022.

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