A Phase III Multicenter, Randomized Study Comparing RIT Vs ASCT in Patients With Relapsed/Refractory (FL)

Sponsor

Fondazione Italiana Linfomi ONLUS (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01827605

Collaborator

(none)

159

Enrollment

Locations

Arms

132

Duration (Months)

4.2

Patients Per Site

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsed Follicular Lymphoma	Other: ZEVALIN Drug: BEAM	Phase 3

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)

Study Design

Study Type:

Interventional

Actual Enrollment :

159 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Oct 1, 2019

Anticipated Study Completion Date :

Jan 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A RIT 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.	Other: ZEVALIN 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). Other Names: RIT
Experimental: ARM B ASCT 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	Drug: BEAM 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 Other Names: ASCT

Arm

Intervention/Treatment

Experimental: Arm A RIT

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.

Other: ZEVALIN

Other Names:

RIT

Experimental: ARM B ASCT

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

Drug: BEAM

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

Other Names:

ASCT

Outcome Measures

Primary Outcome Measures

Progression Free Survival from randomization (rPFS) [36 months]
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) [36 months]
OS will be defined as the time between the date of randomization and the date of death from any cause.
Event Free Survival (EFS) [36 months]
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) [36 months]
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) [42 months]
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) [42 months]
OS will be defined as the time between the date of enrolment and the date of death from any cause
Complete Response (CR) Rate [At the end of the consolidation phase (6 months)]
Proportion of CR according to the Cheson 2007 response criteria at the end of consolidation phase.
Overall Response Rate (ORR) [At the end of the consolidation phase (6 months)]
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 [42 months]
Incidence of grade 3 or higher Toxicity measured by CTCAE v.4.03 during therapy.
Molecular Response rate (MR) [36 months]
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) [6 months]
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) [24 months]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	A.O.U. San Martino	Genova	GE	Italy	16132
2	Ematologia, A.O. San Gerardo	Monza	Milano	Italy	20052
3	A.O. Niguarda	Milano	MI	Italy	20162
4	IRCCS-Centro di riferimento oncologico UO di ematologia e Trapianto Cellule Staminali	Rionero in Vulture	Potenza	Italy	85028
5	Azienda Ospedaliera "Bianchi Melacrino Morelli"	Reggio Calabria	RC	Italy	89125
6	Presidio Ospedaliero "A. Tortora"	Pagani	SA	Italy	84014
7	Emat Univ - Città della salute e della scienza di Torino	Torino	TO	Italy	10126
8	Ospedale San Bortolo	Vicenza	VI	Italy	36100
9	Ospedale Policlinico G.B. Rossi (Borgo Roma) Di Verona	Verona	VR	Italy	37126
10	A.O. SS. Antonio e Biagio e C. Arrigo	Alessandria		Italy	15121
11	Clinica di ematologia AOU Umberto I Ospedali Riuniti	Ancona		Italy	60100
12	Ematologia con Trapianto Policlinico Universitario Consorziale	Bari		Italy	70124
13	Spedali Civili	Brescia		Italy
14	Presidio Ospedaliero A.Perrino - Divisione di Ematologia	Brindisi		Italy
15	Divisione di Ematologia Osp. Businco	Cagliari		Italy
16	IRCC Onco-Ematologia	Candiolo		Italy
17	Ospedale Ferrarotto	Catania		Italy
18	Policlinico Careggi Clinica Ematologica	Firenze		Italy
19	A O Papardo	Messina		Italy
20	Ematologia e Trapianto IRCCS, Istituto Nazionale dei Tumori	Milano		Italy
21	IRCCS San Raffaele Unità di Chemioterapia	Milano		Italy
22	Policlinico di Modena - Università degli studi	Modena		Italy
23	Istituto Pascale Oncoematologia	Napoli		Italy
24	SCDU Ematologia - Università del Piemonte Orientale	Novara		Italy	28100
25	Ospedale S. Francesco	Nuoro		Italy
26	Azienda Ospedaliera V. Cervello	Palermo		Italy	90146
27	U.O. Complessa di Ematologia Ospedale di Parma	Parma		Italy	43100
28	Ematologia Policlinico San Matteo	Pavia		Italy	27100
29	Ospedale Santa Maria della Misericordia	Perugia		Italy
30	Ospedale Santo Spirito Dipartimento di Ematologia	Pescara		Italy
31	Unità Ematologia Ospedale Civile di Piacenza	Piacenza		Italy	29100
32	Ausl Ravenna	Ravenna		Italy
33	SC Ematologia AO Santa Maria Nuova IRCCS	Reggio Emilia		Italy	42123
34	Univeristà La Sapienza	Roma		Italy
35	SC Ematologia Città della salute e della scienza di Torino	Torino		Italy
36	Filippo Gherlizoni	Treviso		Italy
37	UO Ematologia Osp. Cardinale Panico	Tricase		Italy
38	Clinica di Ematologia - A.O.U. S. Maria di Udine	Udine		Italy

Sponsors and Collaborators

Fondazione Italiana Linfomi ONLUS

Investigators

Principal Investigator: Umberto Vitolo, AO Città della salute e della Scienza di Torino - Ospedale S. Giovanni Battista - TORINO
Principal Investigator: Marco Ladetto, AO SS. Antonio e Biagio e Cesare Arrigo Alessandria