Study to Evaluate the Efficacy of Response-adapted Strategy in Follicular Lymphoma

Sponsor

Fondazione Italiana Linfomi ONLUS (Other)

Overall Status

Completed

CT.gov ID

NCT02063685

Collaborator

(none)

807

Enrollment

Locations

Arms

113

Duration (Months)

16.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Recently, the availability of R has substantially changed therapeutic approach to FL patients, since its combination with chemotherapy has improved response rates, progression free survival (PFS) and overall survival (OS). Based on the results of recently completed randomized studies the standard treatment for patients with FL should consist of an initial therapy with R-CHOP combination followed by two-year maintenance with R. Although results of randomized trials confirmed that this approach results in an improved patients' outcome and made a step forward in the management of patients with FL, one important question that can be raised is if this approach is really needed for all patients with FL or if some of them could benefit from a reduced intensity treatment achieving the same results in terms of outcome and survival . This question is of particular interest for newly diagnosed patients for whom maintenance does not affect OS.

More recent data demonstrated that the outcome of patients with FL can be further predicted by evaluating the quality of response to therapy studying minimal residual disease (MRD). This project addresses the objective of evaluating if combining clinical response assessed on FDG-PET scan and molecular response measured through MRD detection could permit to single out groups of patients at different risk of progression and to consequently modulate maintenance therapies, with the aim to provide clinicians a more rational use of the available diagnostic and therapeutic resources.

Condition or Disease	Intervention/Treatment	Phase
Follicular Non-Hodgkin's Lymphoma	Drug: R-CHOP or R-bendamustine Drug: Observation Drug: Maintenance weekly x4 Drug: Ibritumomab Tiuxetan + Maintenance Drug: Standard Maintenance	Phase 3

Detailed Description

This is a multicenter, randomized, phase III, superiority study comparing standard vs response driven approach to maintenance. Adult patients (age ≥ 18 years) with naïve, untreated follicular lymphoma, stage II-IV, Follicular Lymphoma International Prognostic Index 2 (FLIPI2) >0 requiring a therapeutic intervention will be recruited and randomly assigned in a 1:1 ratio to either standard or experimental arm.

All patients will receive the same induction therapy with 6 cycles of R-CHOP or R-bendamustine and 2 additional doses of Rituximab.

At baseline patients will be assessed for molecular status and staged by means of CT scan. A baselineFluorine-18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) scan should also be performed.

At the end of chemoimmunotherapy all patients will be assessed for disease response by common clinical and laboratory examination, CT scan and FDG-PET. An intermediate assessment of response with CT scan and FDG-PET (optional) will also be performed after the first four courses of R-chemoimmunotherapy.

At the end of induction therapy the status of minimal residual disease will be also evaluated.

After induction treatment all responding patients in the standard arm will receive standard maintenance therapy with Rituximab (every 2 months for 2 years), while patients in the experimental arm will be subdivided into two risk groups and assigned to different post induction treatments based on FDG-PET and MRD results. In both arms, patients with stable or progressive disease (PET positive and less than PR on CT scan) will be addressed to salvage treatment chosen at physician discretion.

In the experimental arm, risk group allocation will be performed primarily on the basis of

FDG-PET results:

Group 1 (low risk): negative FDG-PET
Group 2 (high risk): positive FDG-PET

Patients at low risk (FDG-PET negative) will received maintenance therapy according to their

MRD status,particularly:

Group 1a (MRD negative): observation
Group 1b (MRD positive): pre-emptive Rituximab therapy

Patient at high risk (FDG-PET positive) will receive maintenance regardless of their MRD status:

· Group 2: intensified maintenance ((90)Y Ibritumomab Tiuxetan + Rituximab maintenance )

Study Design

Study Type:

Interventional

Actual Enrollment :

807 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multicenter, Phase III, Randomized Study to Evaluate the Efficacy of Response-adapted Strategy to Define Maintenance After Standard Chemoimmunotherapy in Patients With Advanced-stage Follicular Lymphoma.

Study Start Date :

Jul 1, 2012

Actual Primary Completion Date :

Dec 1, 2021

Actual Study Completion Date :

Dec 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Other: GROUP 1 - STANDARD R-CHOP or R-bendamustine + Standard Maintenance	Drug: R-CHOP or R-bendamustine As induction therapy all patients will receive 6 courses of: Rituximab: 375 mg/m² day 1 iv Cyclophosphamide: 750 mg/m² day 1 iv Doxorubicin: 50 mg/m² day 1 iv Vincristine: 1.4 mg/m² day 1 iv (max dose 2mg) Prednisone: 100 mg day 1-5 os To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 21 days. or 6 courses of: Rituximab: 375 mg/m² day 1 iv Bendamustine: 90 mg/m² day 1 and 2 iv. To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 28 days. Other Names: Rituximab Cyclophosphamide, Hydroxydaunorubicin Oncovin Prednisone Bendamustine Drug: Standard Maintenance Rituximab 375 mg/m² every 2 months for 2 years. Maintenance will have to be started no more than 12 weeks after the last induction chemoimmunotherapy infusion. Other Names: Rituximab
Experimental: GROUP 2 FDG-PET POSITIVE (score 4-5) patients (High risk) R-CHOP or R-bendamustine + Ibritumomab Tiuxetan + Maintenance	Drug: R-CHOP or R-bendamustine As induction therapy all patients will receive 6 courses of: Rituximab: 375 mg/m² day 1 iv Cyclophosphamide: 750 mg/m² day 1 iv Doxorubicin: 50 mg/m² day 1 iv Vincristine: 1.4 mg/m² day 1 iv (max dose 2mg) Prednisone: 100 mg day 1-5 os To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 21 days. or 6 courses of: Rituximab: 375 mg/m² day 1 iv Bendamustine: 90 mg/m² day 1 and 2 iv. To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 28 days. Other Names: Rituximab Cyclophosphamide, Hydroxydaunorubicin Oncovin Prednisone Bendamustine Drug: Ibritumomab Tiuxetan + Maintenance single dose of (90)Y Ibritumomab Tiuxetan (0.4 mCi/kg). Following RIT patients will continue maintenance with Rituximab (375 mg/m² every 2 months) for a total of 11 infusions. Other Names: Ibritumomab Tiuxetan
Experimental: GROUP 1a FDG-PET NEGATIVE (score 1-3) AND MRD NEGATIVE R-CHOP or R-bendamustine + Observation	Drug: R-CHOP or R-bendamustine As induction therapy all patients will receive 6 courses of: Rituximab: 375 mg/m² day 1 iv Cyclophosphamide: 750 mg/m² day 1 iv Doxorubicin: 50 mg/m² day 1 iv Vincristine: 1.4 mg/m² day 1 iv (max dose 2mg) Prednisone: 100 mg day 1-5 os To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 21 days. or 6 courses of: Rituximab: 375 mg/m² day 1 iv Bendamustine: 90 mg/m² day 1 and 2 iv. To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 28 days. Other Names: Rituximab Cyclophosphamide, Hydroxydaunorubicin Oncovin Prednisone Bendamustine Drug: Observation not maintenance therapy and followed-up with MRD monitoring.
Experimental: GROUP 1b FDG-PET NEGATIVE (score 1-3) AND MRD POSITIVE R-CHOP or R-bendamustine + Maintenance weekly x4	Drug: R-CHOP or R-bendamustine As induction therapy all patients will receive 6 courses of: Rituximab: 375 mg/m² day 1 iv Cyclophosphamide: 750 mg/m² day 1 iv Doxorubicin: 50 mg/m² day 1 iv Vincristine: 1.4 mg/m² day 1 iv (max dose 2mg) Prednisone: 100 mg day 1-5 os To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 21 days. or 6 courses of: Rituximab: 375 mg/m² day 1 iv Bendamustine: 90 mg/m² day 1 and 2 iv. To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 28 days. Other Names: Rituximab Cyclophosphamide, Hydroxydaunorubicin Oncovin Prednisone Bendamustine Drug: Maintenance weekly x4 Four weekly doses of Rituximab (375 mg/m²). Rituximab could be repeated for MRD positive for a maximum of three courses Other Names: Rituximab

Outcome Measures

Primary Outcome Measures

PFS [12/31/2019]
To evaluate whether a FDG-PET and MRD response-based maintenance therapy is more effective in terms of Progression-Free Survival (PFS) than a standard maintenance therapy with Rituximab in patients with untreated, advanced, follicular lymphoma. Progression Free Survival (PFS) PFS will be measured from the date of randomization to the date of documented first occurrence of disease progression or relapse or to the date of death from any cause. Responding patients and patients who are lost to follow up will be censored at their last assessment date.

Secondary Outcome Measures

CRR [12/31/2019]
Complete Response Rate (CRR) is defined as the number of CR after the completion of the study treatment. Patients without a response assessment (due to any reasons) will be considered as non-responders.
ORR [12/31/2019]
Overall Response Rate (ORR) after the completion of the treatment, defined as the sum of Complete Response and Partial Response. Patients without a response assessment (due to any reasons) will be considered as non-responders.
DR [12/31/2019]
Duration of Response (DR) is from the time when criteria for response (ie, CR or PR) are met, to the first documentation of relapse or progression.
EFS [12/31/2019]
Event Free Survival (EFS) is measured from the time from study entry to any treatment failure including disease progression, or discontinuation of treatment for any reason (eg, disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death).
OS [12/31/2019]
Overall survival (OS) is defined as the time from the first day of study treatment until the date of death irrespective of cause. Patients who have not died at the time of end of the whole study , and patients who are lost to follow up , will be censored at the date of the last contact.
Molecular response analysis [12/31/2019]
Rate of molecular remission will be defined as the proportion of patients polymerase chain reaction (PCR) negative for Bcl2/IgH at different time-points including those achieving continuous MR in two or more consecutive time-points. Patients without a response assessment (due to any reasons) will be excluded from the analysis. Rate of conversion will be defined as the proportion of patients from baseline PCR-positivity to PCR-negativity. Patients without a response assessment (due to any reasons) will be excluded from the analysis. Rate of molecular relapse will be defined as the proportion of patients from PCR-negativity to PCR-positivity. Patients without a response assessment (due to any reasons) will be excluded from the analysis.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Histological diagnosis of B-Cell CD20+ Follicular Lymphoma (FL), grade I, II, IIIa according to the WHO 2008 classification
ECOG performance status 0-2
Age ≥ 18 years
Ann Arbor stage II-IV
FLIPI2>0
Presence of evaluable/measurable disease after diagnostic biopsy
At least one of the following criteria for defining active disease:
systemic symptoms
cytopenia due to bone marrow involvement
LDH> upper normal value
any nodal or extranodal tumor mass with a diameter >7cm
involvement of ≥ 3 nodal sites, each with a diameter of ≥ 3cm
extranodal disease
rapidly progressive disease
Life expectancy > 6 months
Left ventricular ejection fraction (LVEF) ³ 50%
Serum negativity for HIV
Serum negativity for HBsAg; HBcAb positive but HBV-DNA negative patients are allowed with mandatory Lamivudine prophylaxis.
Serum negativity for HCV, except for those patients without signs of active viral replication assessed by HCV-RNA copies
Serum creatinine < 2mg/dl , serum bilirubin < 1.5mg/dl, aspartate amino-transferase (AST/GOT) £ 2.5xUNV, alanine amino-transferase (ALT/GPT) £ 2.5xUNV, and alkaline phosphatase £ 4 times the upper limit of normal (unless the increase is attributed directly to the presence of tumour by the Investigator)
Patients with no previous treatment for the lymphoma with the exception of locoregional radiotherapy (IFRT)
Adequate measure adoption to avoid pregnancy
Written informed consent given at time of registration
Patient must be accessible for treatment and follow up.

Exclusion Criteria:

Histological diagnosis of :
any lymphoma other than follicular lymphoma and all CD20 negative B-cell lymphomas
grade III b follicular lymphoma
evidence of transformation to high grade lymphoma
Ann Arbor stage I
Suspect or clinical evidence of CNS involvement by lymphoma
History of other malignancies within 5 years prior to study entry except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer, low grade, early stage localized prostate cancer treated surgically with curative intent, good prognosis DCIS of the breast treated with lumpectomy alone with curative intent
Evidence of any severe active acute or chronic infection
Concurrent co-morbid medical condition which might exclude administration of full dose chemotherapy
Severe chronic obstructive pulmonary disease with hypoxemia
Severe diabetes mellitus difficult to control with adequate insulin therapy
Myocardial infarction within 6 months before study entry
Clinically significant secondary cardiovascular disease e.g. uncontrolled hypertension, (resting diastolic blood pressure >115 mmHg), uncontrolled multifocal cardiac arrhythmias, symptomatic angina pectoris or congestive cardiac failure NYHA class III-IV
HbsAg-positive, HIV-positive, or HCVAb-positive patients
Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins
Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent
Follicular lymphoma, showing a negative baseline PET scan.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori - Sede Di Meldola (Fc)	Meldola	Forlì Cesena	Italy	47014
2	ASUR 8	Civitanova Marche	Macerata	Italy	62012
3	Irccs Istituto Clinico Humanitas	Rozzano	Milano	Italy	20089
4	Fondazione IRCCS Milano INT	Milano	MI	Italy	20133
5	Azienda Ospedaliera S. Gerardo Di Monza	Monza	Monza Brianza	Italy	20900
6	Irccs Centro Di Riferimento Oncologico Di Basilicata (Crob)	Rionero in Vulture	Potenza	Italy	85028
7	P.O. Umberto I	Nocera Inferiore	Salerno	Italy	84014
8	Fondazione Del Piemonte Per L'Oncologia Ircc Di Candiolo	Candiolo	Torino	Italy	10060
9	A.O. S. Maria di Terni	Terni	TR	Italy	05100
10	Ospedale Civile Ss. Antonio E Biagio Di Alessandria - Alessandria (Al)	Alessandria		Italy	15121
11	A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona _	Ancona		Italy	60126
12	A.O. Universitaria Ospedale Consorziale Policlinico Di Bari	Bari		Italy	70124
13	A.O. Ospedale Degli Infermi	Biella		Italy	13900
14	A.O. Universitaria Policlinico S.Orsola-Malpighi Di Bologna	Bologna		Italy	40138
15	Pres.Ospedal.Spedali Civili Brescia	Brescia		Italy	25125
16	Stabilimento "Perrino" - Brindisi -	Brindisi		Italy	72100
17	Ospedale Armando Businco - Cagliari	Cagliari		Italy	09121
18	A.O. Universitaria Ospedale Vittorio Emanuele Di Catania	Catania		Italy	95124
19	Azienda Ospedaliera S. Croce E Carle Di Cuneo	Cuneo		Italy	12100
20	A.O. Universitaria Careggi Di Firenze	Firenze		Italy	50139
21	A.O. Universitaria S. Martino Di Genova	Genova		Italy	16132
22	Ematologia Ospedale Vito Fazzi	Lecce		Italy
23	Presidio Ospedaliero - Matera -	Matera		Italy	75100
24	Azienda Ospedaliera Papardo	Messina		Italy	98158
25	Irccs Ospedale Maggiore Policlinico Di Milano	Milano		Italy	20122
26	Ospedale Ca' Granda-Niguarda	Milano		Italy	20162
27	A.O. Universitaria Policlinico Di Modena	Modena		Italy	41124
28	Irccs Istituto Nazionale Tumori Fondazione Pascale	Napoli		Italy
29	A.O. Universitaria Maggiore Della Carita' Di Novara	Novara		Italy	28100
30	Ospedale San Francesco	Nuoro		Italy	08100
31	A.O. Universitaria Policlinico Giaccone Di Palermo	Palermo		Italy	90127
32	A.O. "V. Cervello"	Palermo		Italy	90146
33	A O Universitaria di Parma	Parma		Italy
34	IRCCS Policlinico S. Matteo	Pavia		Italy	27100
35	Azienda Ospedaliera Di Perugia - Ospedale S. Maria Della Misericordia -	Perugia		Italy	06134
36	Ospedale Civile Spirito Santo	Pescara		Italy	65124
37	Ausl Di Piacenza	Piacenza		Italy	29121
38	A.O. Universitaria Pisana	Pisa		Italy	56126
39	Ospedale Bianchi - Melacrino - Morelli	Reggio Calabria		Italy	89123
40	Ausl Di Rimini	Rimini		Italy	47924
41	Universita' Degli Studi Di Roma 'La Sapienza'	Roma		Italy	00185
42	Casa sollievo della Sofferenza	San Giovanni Rotondo		Italy
43	A.O. Universitaria Senese	Siena		Italy	53100
44	A.O. Universitaria S. Giovanni Battista-Molinette Di Torino	Torino		Italy	10126
45	Ospedale Ca Foncello	Treviso		Italy
46	A.O.Cardinale Panico Ematologia e centro trapianti	Tricase (LE)		Italy
47	A.O. Universitaria S. Maria Della Misericordia Di Udine	Udine		Italy	33100
48	Ospedale Di Circolo E Fondazione Macchi	Varese		Italy	21100

Sponsors and Collaborators

Fondazione Italiana Linfomi ONLUS

Investigators

Principal Investigator: Donato Mannina, MD, Hematology, Azienda Ospedali Riuniti Papardo-Piemonte, Messina, Italy.
Principal Investigator: Massimo Federico, MD, Department of Diagnostic Medicine, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena , Italy