Back to resultsA Phase III Multicenter, Randomized Study Comparing RIT Vs ASCT in Patients With Relapsed/Refractory (FL)
Primary Purpose
Relapsed Follicular Lymphoma
Status
Active
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
ZEVALIN
BEAM
Sponsored by
About this trial
This is an interventional treatment trial for Relapsed Follicular Lymphoma focused on measuring Relapsed follicular Lymphoma, RIT, Zevalin
Eligibility Criteria
Inclusion Criteria:
- Age 18-65
- Histologically documented diagnosis of grade I-IIIa FL defined according to WHO guidelines 2008 (Re-biopsy required)
- Availability of BM and PB for Minimal Residual Disease (MRD) analysis (see Appendix I)
- Relapsed or refractory disease after ≤ two chemotherapy lines at least one containing Rituximab (Rituximab maintenance is UNOTU considered a therapeutic line)
- Clinical indication of treatment i.e. Stage II-IV who require therapy according to SIE and GELF criteria (see Appendix II)
- ECOG performance status 0-2 (unless disease-related) (see Appendix III)
- Availability of histological material for centralized revision
Laboratory values:
- ANC ≥ 1500/mmc unless due to marrow involvement by lymphoma and/or platelets ≥ 100000/mmc unless due to marrow involvement by lymphoma
- Serum creatinine ≤ 1.5 x ULN, unless it is disease related
- Bilirubin ≤ 1.5 x ULN (or ≤ 3.0 x ULN, if patient has Gilbert syndrome)
- AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN if not lymphoma related or ≤ 5.0 x ULN in case of lymphoma liver involvement
- Adequate cardiac function: LVEF > 50% by echocardiography or MUGA scan
- Not pregnant or breast-feeding
- Willingness to use effective contraception during the study and 3 months after the end of treatment
- No other prior malignancies except for adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, or other cancer from which the patient has been disease-free for ≥ 5 years (see Exclusion criteria 14)
- Signed informed written consent
Exclusion Criteria:
- Grade IIIb FL, transformed FL or histologies different from FL
- Previous treatment with > two lines of chemotherapy ± rituximab Maintenance is UNOTU considered a therapeutics line)
- Previous ASCT or RIT treatment
- CNS involvement by lymphoma
- HBV positivity with the exception of patients who are seropositive because of hepatitis B virus vaccination and patients HbcAb positive and HbsAg negative with undetectable serum HBV-DNA. Occult carriers: must receive treatment with Lamivudine 100 mg for the duration of treatment program and at least 12 months after treatment cessation; HBV-DNA levels and HBsAg will be monitored every month
- HCV positivity with elevated transaminases or INR or APTT or active virus replication
- HIV positivity
- Any concurrent medical condition requiring long term use (> one month) of systemic corticosteroids
- Active bacterial, viral, or fungal infection requiring systemic therapy
- Any concurrent medical or psychiatric condition which might impair administration of therapy or preclude the ability to give informed consent
- Treatment with an experimental agent within 30 days prior to study entry
- Myelosuppressive chemo or biological therapy within three weeks before study entry (use rituximab course delivered as maintenance is not an exclusion therapy)
- Major surgery other than diagnosis within 4 weeks prior to study entry
- Previous i.v. or i.m. treatments with murine or animal derived antibodies
Sites / Locations
- A.O.U. San Martino
- Ematologia, A.O. San Gerardo
- A.O. Niguarda
- IRCCS-Centro di riferimento oncologico UO di ematologia e Trapianto Cellule Staminali
- Azienda Ospedaliera "Bianchi Melacrino Morelli"
- Presidio Ospedaliero "A. Tortora"
- Emat Univ - Città della salute e della scienza di Torino
- Ospedale San Bortolo
- Ospedale Policlinico G.B. Rossi (Borgo Roma) Di Verona
- A.O. SS. Antonio e Biagio e C. Arrigo
- Clinica di ematologia AOU Umberto I Ospedali Riuniti
- Ematologia con Trapianto Policlinico Universitario Consorziale
- Spedali Civili
- Presidio Ospedaliero A.Perrino - Divisione di Ematologia
- Divisione di Ematologia Osp. Businco
- IRCC Onco-Ematologia
- Ospedale Ferrarotto
- Policlinico Careggi Clinica Ematologica
- A O Papardo
- Ematologia e Trapianto IRCCS, Istituto Nazionale dei Tumori
- IRCCS San Raffaele Unità di Chemioterapia
- Policlinico di Modena - Università degli studi
- Istituto Pascale Oncoematologia
- SCDU Ematologia - Università del Piemonte Orientale
- Ospedale S. Francesco
- Azienda Ospedaliera V. Cervello
- U.O. Complessa di Ematologia Ospedale di Parma
- Ematologia Policlinico San Matteo
- Ospedale Santa Maria della Misericordia
- Ospedale Santo Spirito Dipartimento di Ematologia
- Unità Ematologia Ospedale Civile di Piacenza
- Ausl Ravenna
- SC Ematologia AO Santa Maria Nuova IRCCS
- Univeristà La Sapienza
- SC Ematologia Città della salute e della scienza di Torino
- Filippo Gherlizoni
- UO Ematologia Osp. Cardinale Panico
- Clinica di Ematologia - A.O.U. S. Maria di Udine
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Arm A RIT
ARM B ASCT
Arm Description
Infusion of 90Y Ibritumomab Tiuxetan if the patient has less than 25% BM infiltration at the pre-consolidation restaging (0.4 mCi/kg if platelets ≥150,000/mmc, 0.3 mCi/kg if platelets are between 100.000 and 150,000/mmc). Zevalin® will be delivered as per indications and should thus be provided at expenses following regular supplies procedures.
BEAM conditioning regimen (or in alternative FEAM regimen with fotemustine to replace BCNU) and reinfusion of CD34+ cells of ≥ 2x106/Kg CD34+ day 0 (optimal dose to reinfuse 4x106/Kg CD34+). G-CSF 5 mcg/Kg from day 2 until ANC>1500/mmc. Patients who failed mobilization will directly proceed to rituximab maintenance
Outcomes
Primary Outcome Measures
Progression Free Survival from randomization (rPFS)
PFS will be defined as the time between the date of randomization and the date of disease progression, relapse or death from any cause.
Secondary Outcome Measures
Overall Survival from randomization (rOS)
OS will be defined as the time between the date of randomization and the date of death from any cause.
Event Free Survival (EFS)
EFS will be measured from the date of randomization to the date of any treatment failure including death, disease progression or relapse, discontinuation of treatment for any reason (toxicity, patient preference, initiation of new treatment without documented progression).
Treatment Free Survival from randomization (TFS)
TFS will be defined as the time between the date of the end of primary treatment until the institution of the next unplanned chemotherapy in randomized population.
Progression Free Survival from enrolment (ePFS)
PFS will be defined as the time between the date of enrolment and the date of disease progression, relapse or death from any cause.
Overall Survival from enrolment (eOS)
OS will be defined as the time between the date of enrolment and the date of death from any cause
Complete Response (CR) Rate
Proportion of CR according to the Cheson 2007 response criteria at the end of consolidation phase.
Overall Response Rate (ORR)
ORR at the end of the consolidation phase is defined as Complete Response (CR) or Partial Response according to the Cheson 2007 response criteria.
Toxicity
Incidence of grade 3 or higher Toxicity measured by CTCAE v.4.03 during therapy.
Molecular Response rate (MR)
Rate of MR will be defined as the proportion of patients achieving PCR negativity after the consolidation phase and during follow up.
Molecular Response rate conversion (cMR)
Rate of conversion will be defined as the proportion of patients with baseline PCR-positivity converting to PCR-negativity during treatment.
Molecular Relapse Rate (MRR)
Rate of molecular relapse will be defined as the proportion of patients with PCR-negativity after treatment converting to PCR-positivity during the first two years of follow-up.
Full Information
NCT ID
NCT01827605
First Posted
April 5, 2013
Last Updated
September 13, 2023
Sponsor
Fondazione Italiana Linfomi - ETS
1. Study Identification
Unique Protocol Identification Number
NCT01827605
Brief Title
A Phase III Multicenter, Randomized Study Comparing RIT Vs ASCT in Patients With Relapsed/Refractory (FL)
Official Title
A Phase III Multicenter,Randomized Study Comparing Consolidation With 90yttrium-Labeled Ibritumomab Tiuxetan (Zevalin®) Radioimmunotherapy Vs Autologous Stem Cell Transplantation (ASCT) in Patients With Relapsed/Refractory Follicular Lymphoma (FL) Aged 18-65 Years
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 2012 (undefined)
Primary Completion Date
October 2019 (Actual)
Study Completion Date
January 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fondazione Italiana Linfomi - ETS
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a Phase III, multicenter, open-label, randomized and controlled study to compare the efficacy of a consolidation therapy with RIT versus ASCT in patients with FL in CR or PR after second or third line chemotherapy supplemented with rituximab.
Detailed Description
This is a Phase III, multicenter, open-label, randomized and controlled study to compare the efficacy of a consolidation therapy with RIT vs. ASCT in patients with FL in CR or PR after second or third line chemotherapy supplemented with rituximab. Patients with FL will be eligible for screening at the time of relapsed or refractory disease after two or less chemotherapy lines at least one containing rituximab.
This study will be conducted in six steps as follows. Screening Phase, Enrolment and Induction chemotherapy (STEP I) Randomization (STEP II) Stem cell mobilization and collection (STEP III) Consolidation (RIT vs ASCT) (STEP IV) Maintenance (STEP V) Follow-up Phase (STEP VI)
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsed Follicular Lymphoma
Keywords
Relapsed follicular Lymphoma, RIT, Zevalin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
159 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm A RIT
Arm Type
Experimental
Arm Description
Infusion of 90Y Ibritumomab Tiuxetan if the patient has less than 25% BM infiltration at the pre-consolidation restaging (0.4 mCi/kg if platelets ≥150,000/mmc, 0.3 mCi/kg if platelets are between 100.000 and 150,000/mmc). Zevalin® will be delivered as per indications and should thus be provided at expenses following regular supplies procedures.
Arm Title
ARM B ASCT
Arm Type
Experimental
Arm Description
BEAM conditioning regimen (or in alternative FEAM regimen with fotemustine to replace BCNU) and reinfusion of CD34+ cells of ≥ 2x106/Kg CD34+ day 0 (optimal dose to reinfuse 4x106/Kg CD34+). G-CSF 5 mcg/Kg from day 2 until ANC>1500/mmc. Patients who failed mobilization will directly proceed to rituximab maintenance
Intervention Type
Other
Intervention Name(s)
ZEVALIN
Other Intervention Name(s)
RIT
Intervention Description
Infusion of 90Y Ibritumomab Tiuxetan if the patient has less than 25% BM infiltration at the pre-consolidation restaging (0.4 mCi/kg if platelets ≥150,000/mmc, 0.3 mCi/kg if platelets are between 100.000 and 150,000/mmc).
Intervention Type
Drug
Intervention Name(s)
BEAM
Other Intervention Name(s)
ASCT
Intervention Description
BEAM REGIMEN day -6 Carmustine* 300 mg/ m2 i.v. in 250ml dextrose 5% solution
from day -5 to day -2 Cytarabine 200 mg/m2 i.v. every 12 hours in 250 ml dextrose 5% solution, 250 ml/hr Etoposide 100 mg/m2 i.v. every 12 hours in 250 ml dextrose 5% solution, 250 ml/hr day -1 Melphalan 140 mg/m2 i.v. in 100ml saline solution in 200 ml/hr
day 0
UReinfusion of autologous stem cells following this rules:
Patient collecting ≥6x106 CD34+ cells/kg use >4x106 CD34+ cells/kg for ASCT and keep >2x106 CD34+ cells/kg for back up;
Patient collecting 4-6x106 CD34+ cells/kg use >2x106 CD34+ cells/kg for ASCT and keep >2x106 CD34+ cells/kg for back up;
Patient collecting 2-4x106 CD34+ cells/kg use all CD34+ cells for ASCT and keep no back up.
day 2 Filgrastim or Lenograstim 5μg/Kg s.c. until ANC > 1500/mmc
Primary Outcome Measure Information:
Title
Progression Free Survival from randomization (rPFS)
Description
PFS will be defined as the time between the date of randomization and the date of disease progression, relapse or death from any cause.
Time Frame
36 months
Secondary Outcome Measure Information:
Title
Overall Survival from randomization (rOS)
Description
OS will be defined as the time between the date of randomization and the date of death from any cause.
Time Frame
36 months
Title
Event Free Survival (EFS)
Description
EFS will be measured from the date of randomization to the date of any treatment failure including death, disease progression or relapse, discontinuation of treatment for any reason (toxicity, patient preference, initiation of new treatment without documented progression).
Time Frame
36 months
Title
Treatment Free Survival from randomization (TFS)
Description
TFS will be defined as the time between the date of the end of primary treatment until the institution of the next unplanned chemotherapy in randomized population.
Time Frame
36 months
Title
Progression Free Survival from enrolment (ePFS)
Description
PFS will be defined as the time between the date of enrolment and the date of disease progression, relapse or death from any cause.
Time Frame
42 months
Title
Overall Survival from enrolment (eOS)
Description
OS will be defined as the time between the date of enrolment and the date of death from any cause
Time Frame
42 months
Title
Complete Response (CR) Rate
Description
Proportion of CR according to the Cheson 2007 response criteria at the end of consolidation phase.
Time Frame
At the end of the consolidation phase (6 months)
Title
Overall Response Rate (ORR)
Description
ORR at the end of the consolidation phase is defined as Complete Response (CR) or Partial Response according to the Cheson 2007 response criteria.
Time Frame
At the end of the consolidation phase (6 months)
Title
Toxicity
Description
Incidence of grade 3 or higher Toxicity measured by CTCAE v.4.03 during therapy.
Time Frame
42 months
Title
Molecular Response rate (MR)
Description
Rate of MR will be defined as the proportion of patients achieving PCR negativity after the consolidation phase and during follow up.
Time Frame
36 months
Title
Molecular Response rate conversion (cMR)
Description
Rate of conversion will be defined as the proportion of patients with baseline PCR-positivity converting to PCR-negativity during treatment.
Time Frame
6 months
Title
Molecular Relapse Rate (MRR)
Description
Rate of molecular relapse will be defined as the proportion of patients with PCR-negativity after treatment converting to PCR-positivity during the first two years of follow-up.
Time Frame
24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 18-65
Histologically documented diagnosis of grade I-IIIa FL defined according to WHO guidelines 2008 (Re-biopsy required)
Availability of BM and PB for Minimal Residual Disease (MRD) analysis (see Appendix I)
Relapsed or refractory disease after ≤ two chemotherapy lines at least one containing Rituximab (Rituximab maintenance is UNOTU considered a therapeutic line)
Clinical indication of treatment i.e. Stage II-IV who require therapy according to SIE and GELF criteria (see Appendix II)
ECOG performance status 0-2 (unless disease-related) (see Appendix III)
Availability of histological material for centralized revision
Laboratory values:
ANC ≥ 1500/mmc unless due to marrow involvement by lymphoma and/or platelets ≥ 100000/mmc unless due to marrow involvement by lymphoma
Serum creatinine ≤ 1.5 x ULN, unless it is disease related
Bilirubin ≤ 1.5 x ULN (or ≤ 3.0 x ULN, if patient has Gilbert syndrome)
AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN if not lymphoma related or ≤ 5.0 x ULN in case of lymphoma liver involvement
Adequate cardiac function: LVEF > 50% by echocardiography or MUGA scan
Not pregnant or breast-feeding
Willingness to use effective contraception during the study and 3 months after the end of treatment
No other prior malignancies except for adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, or other cancer from which the patient has been disease-free for ≥ 5 years (see Exclusion criteria 14)
Signed informed written consent
Exclusion Criteria:
Grade IIIb FL, transformed FL or histologies different from FL
Previous treatment with > two lines of chemotherapy ± rituximab Maintenance is UNOTU considered a therapeutics line)
Previous ASCT or RIT treatment
CNS involvement by lymphoma
HBV positivity with the exception of patients who are seropositive because of hepatitis B virus vaccination and patients HbcAb positive and HbsAg negative with undetectable serum HBV-DNA. Occult carriers: must receive treatment with Lamivudine 100 mg for the duration of treatment program and at least 12 months after treatment cessation; HBV-DNA levels and HBsAg will be monitored every month
HCV positivity with elevated transaminases or INR or APTT or active virus replication
HIV positivity
Any concurrent medical condition requiring long term use (> one month) of systemic corticosteroids
Active bacterial, viral, or fungal infection requiring systemic therapy
Any concurrent medical or psychiatric condition which might impair administration of therapy or preclude the ability to give informed consent
Treatment with an experimental agent within 30 days prior to study entry
Myelosuppressive chemo or biological therapy within three weeks before study entry (use rituximab course delivered as maintenance is not an exclusion therapy)
Major surgery other than diagnosis within 4 weeks prior to study entry
Previous i.v. or i.m. treatments with murine or animal derived antibodies
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Umberto Vitolo
Organizational Affiliation
AO Città della salute e della Scienza di Torino - Ospedale S. Giovanni Battista - TORINO
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Marco Ladetto
Organizational Affiliation
AO SS. Antonio e Biagio e Cesare Arrigo Alessandria
Official's Role
Principal Investigator
Facility Information:
Facility Name
A.O.U. San Martino
City
Genova
State/Province
GE
ZIP/Postal Code
16132
Country
Italy
Facility Name
Ematologia, A.O. San Gerardo
City
Monza
State/Province
Milano
ZIP/Postal Code
20052
Country
Italy
Facility Name
A.O. Niguarda
City
Milano
State/Province
MI
ZIP/Postal Code
20162
Country
Italy
Facility Name
IRCCS-Centro di riferimento oncologico UO di ematologia e Trapianto Cellule Staminali
City
Rionero in Vulture
State/Province
Potenza
ZIP/Postal Code
85028
Country
Italy
Facility Name
Azienda Ospedaliera "Bianchi Melacrino Morelli"
City
Reggio Calabria
State/Province
RC
ZIP/Postal Code
89125
Country
Italy
Facility Name
Presidio Ospedaliero "A. Tortora"
City
Pagani
State/Province
SA
ZIP/Postal Code
84014
Country
Italy
Facility Name
Emat Univ - Città della salute e della scienza di Torino
City
Torino
State/Province
TO
ZIP/Postal Code
10126
Country
Italy
Facility Name
Ospedale San Bortolo
City
Vicenza
State/Province
VI
ZIP/Postal Code
36100
Country
Italy
Facility Name
Ospedale Policlinico G.B. Rossi (Borgo Roma) Di Verona
City
Verona
State/Province
VR
ZIP/Postal Code
37126
Country
Italy
Facility Name
A.O. SS. Antonio e Biagio e C. Arrigo
City
Alessandria
ZIP/Postal Code
15121
Country
Italy
Facility Name
Clinica di ematologia AOU Umberto I Ospedali Riuniti
City
Ancona
ZIP/Postal Code
60100
Country
Italy
Facility Name
Ematologia con Trapianto Policlinico Universitario Consorziale
City
Bari
ZIP/Postal Code
70124
Country
Italy
Facility Name
Spedali Civili
City
Brescia
Country
Italy
Facility Name
Presidio Ospedaliero A.Perrino - Divisione di Ematologia
City
Brindisi
Country
Italy
Facility Name
Divisione di Ematologia Osp. Businco
City
Cagliari
Country
Italy
Facility Name
IRCC Onco-Ematologia
City
Candiolo
Country
Italy
Facility Name
Ospedale Ferrarotto
City
Catania
Country
Italy
Facility Name
Policlinico Careggi Clinica Ematologica
City
Firenze
Country
Italy
Facility Name
A O Papardo
City
Messina
Country
Italy
Facility Name
Ematologia e Trapianto IRCCS, Istituto Nazionale dei Tumori
City
Milano
Country
Italy
Facility Name
IRCCS San Raffaele Unità di Chemioterapia
City
Milano
Country
Italy
Facility Name
Policlinico di Modena - Università degli studi
City
Modena
Country
Italy
Facility Name
Istituto Pascale Oncoematologia
City
Napoli
Country
Italy
Facility Name
SCDU Ematologia - Università del Piemonte Orientale
City
Novara
ZIP/Postal Code
28100
Country
Italy
Facility Name
Ospedale S. Francesco
City
Nuoro
Country
Italy
Facility Name
Azienda Ospedaliera V. Cervello
City
Palermo
ZIP/Postal Code
90146
Country
Italy
Facility Name
U.O. Complessa di Ematologia Ospedale di Parma
City
Parma
ZIP/Postal Code
43100
Country
Italy
Facility Name
Ematologia Policlinico San Matteo
City
Pavia
ZIP/Postal Code
27100
Country
Italy
Facility Name
Ospedale Santa Maria della Misericordia
City
Perugia
Country
Italy
Facility Name
Ospedale Santo Spirito Dipartimento di Ematologia
City
Pescara
Country
Italy
Facility Name
Unità Ematologia Ospedale Civile di Piacenza
City
Piacenza
ZIP/Postal Code
29100
Country
Italy
Facility Name
Ausl Ravenna
City
Ravenna
Country
Italy
Facility Name
SC Ematologia AO Santa Maria Nuova IRCCS
City
Reggio Emilia
ZIP/Postal Code
42123
Country
Italy
Facility Name
Univeristà La Sapienza
City
Roma
Country
Italy
Facility Name
SC Ematologia Città della salute e della scienza di Torino
City
Torino
Country
Italy
Facility Name
Filippo Gherlizoni
City
Treviso
Country
Italy
Facility Name
UO Ematologia Osp. Cardinale Panico
City
Tricase
Country
Italy
Facility Name
Clinica di Ematologia - A.O.U. S. Maria di Udine
City
Udine
Country
Italy
12. IPD Sharing Statement
Learn more about this trial
A Phase III Multicenter, Randomized Study Comparing RIT Vs ASCT in Patients With Relapsed/Refractory (FL)
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