"MIRO" Molecularly Oriented Immuno-radio-therapy

NCT02710643 | Completed Phase 2

• 1 other identifier: FIL_MIRO
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 27

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

Conditions

Follicular Lymphoma, Grade 1; Follicular Lymphoma, Grade 2; Follicular Lymphoma Grade 3A

Keywords

Follicular; Lymphoma; Grade 1; Grade 2; Grade 3A

Outcome Measures

Primary Outcomes (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

  4 YEARS FROM ENROLLMENT

Secondary Outcomes (6)

• Clinical response rate

  4 YEARS FROM ENROLLMENT

• Overall response

  4 YEARS FROM ENROLLMENT

• Partial response

  4 YEARS FROM ENROLLMENT

• Complete response

  4 YEARS FROM ENROLLMENT

• Progression Free Survival

  4 YEARS FROM ENROLLMENT

Study Arms (3)

MRD - BEFORE RT

NO INTERVENTION

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.

MRD + BEFORE RT AND MRD - AFTER RT

NO INTERVENTION

Patients 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 RT

EXPERIMENTAL

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

Interventions

OFATUMUMAB DRUG

8 weekly infusion of 1000 mg total dose

Also known as: ARZERRA

MRD + BEFORE RT AND MRD + AFTER RT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Fondazione Italiana Linfomi - ETS: lead

Study Sites (27)

Ospedale SS. Antonio e Biagio e Cesare Arrigo

Alessandria, AL, 15121, Italy

Location

Ematologia Azienda Ospedaliera Policlinico

Bari, BA, Italy

Location

A.O. Spedali Civili

Brescia, BS, 25100, Italy

Location

A.O. Niguarda

Milan, MI, 20162, Italy

Location

Azienda Ospedaliera S. Gerardo Di Monza

Monza, Monza Brianza, 20900, Italy

Location

Osp. S. Maria delle Croci

Ravenna, RA, 48121, Italy

Location

A.O. Bianchi - Melacrino - Morelli

Reggio Calabria, RC, 89125, Italy

Location

Polo Pontino

Latina, Roma, 04100, Italy

Location

Ospedale di Matera

Matera, 75100, Italy

Location

Area Vasta Romagna e IRST

Meldola (FC), Italy

Location

Ospedali Riuniti Papardo

Messina, 98158, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

Milan, 120133, Italy

Location

Ospedale S. Raffaele

Milan, 20132, Italy

Location

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

Novara, Italy

Location

U.O. Complessa di Ematologia Ospedale di Parma

Parma, 43100, Italy

Location

IRCCS Policlinico S. Matteo di Pavia

Pavia, 27100, Italy

Location

Ausl Di Piacenza

Piacenza, 29121, Italy

Location

Azienda Ospedaliero Universitaria Pisana U.O. Ematologia

Pisa, Italy

Location

AO Santa Maria Nuova

Reggio Emilia, 42123, Italy

Location

Ausl Di Rimini

Rimini, 47924, Italy

Location

Ematologia e Trapianto Istituto Regina Elena IFO

Roma, Italy

Location

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

Roma, Italy

Location

Ospedale civile DH oncologico

Sassuolo (MO), Italy

Location

Policlinico Le Scotte Clinica Ematologica

Siena, Italy

Location

SC Oncoematologia con autotrapianto AO Santa Maria

Terni, 05100, Italy

Location

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

Torino, 10126, Italy

Location

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

Torino, 10126, Italy

Location

Related Publications (18)

• 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.

  PMID: 8433390 BACKGROUND

• 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.

  PMID: 16401710 BACKGROUND

• 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.

  PMID: 10653868 BACKGROUND

• 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.

  PMID: 9704731 BACKGROUND

• 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.

  PMID: 16154848 BACKGROUND

• 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.

  PMID: 8315432 BACKGROUND

• 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.

  PMID: 16223776 BACKGROUND

• 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.

  PMID: 7237385 BACKGROUND

• 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.

  PMID: 3657890 BACKGROUND

• 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.

  PMID: 17697968 BACKGROUND

• 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.

  PMID: 839876 BACKGROUND

• 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.

  PMID: 1944436 BACKGROUND

• 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.

  PMID: 9597135 BACKGROUND

• 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.

  PMID: 15084619 BACKGROUND

• 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.

  PMID: 10216105 BACKGROUND

• Rambaldi A, Lazzari M, Manzoni C, Carlotti E, Arcaini L, Baccarani M, Barbui T, Bernasconi C, Dastoli G, Fuga G, Gamba E, Gargantini L, Gattei V, Lauria F, Lazzarino M, Mandelli F, Morra E, Pulsoni A, Ribersani M, Rossi-Ferrini PL, Rupolo M, Tura S, Zagonel V, Zaja F, Zinzani P, Reato G, Foa R. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma. Blood. 2002 Feb 1;99(3):856-62. doi: 10.1182/blood.v99.3.856.

  PMID: 11806987 BACKGROUND

• van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. doi: 10.1182/blood-2006-05-021113. Epub 2006 Jul 27.

  PMID: 16873669 BACKGROUND

• Pulsoni A, Starza ID, Frattarelli N, Ghia E, Carlotti E, Cavalieri E, Matturro A, Tempera S, Rambaldi A, Foa R. Stage I/II follicular lymphoma: spread of bcl-2/IgH+ cells in blood and bone marrow from primary site of disease and possibility of clearance after involved field radiotherapy. Br J Haematol. 2007 May;137(3):216-20. doi: 10.1111/j.1365-2141.2007.06545.x.

  PMID: 17408460 BACKGROUND

MeSH Terms

Conditions

Lymphoma, Follicular; Lymphoma

Interventions

ofatumumab

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Alessandro Pulsoni, MD

  Policlinico Umberto I - Università "La Sapienza" - Istituto Ematologia

  STUDY CHAIR

Study Design

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

Study Record Dates

• First Submitted: February 26, 2016
• First Posted: March 17, 2016
• Study Start: October 1, 2014
• Primary Completion: April 1, 2018
• Study Completion: April 7, 2022
• Last Updated: June 21, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will share

Locations

IT (27)