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

Relapsed Follicular Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01827605
• Other study ID #: FIL_FLAZ-12
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: January 2012
• Est. completion date: January 2024

Study information

• Verified date: December 2023
• Source: Fondazione Italiana Linfomi - ETS
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 159
• Est. completion date: January 2024
• Est. primary completion date: October 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Follicular
• Relapsed Follicular Lymphoma

Intervention

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).

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

Locations

Country	Name	City	State
Italy	A.O. SS. Antonio e Biagio e C. Arrigo	Alessandria
Italy	Clinica di ematologia AOU Umberto I Ospedali Riuniti	Ancona
Italy	Ematologia con Trapianto Policlinico Universitario Consorziale	Bari
Italy	Spedali Civili	Brescia
Italy	Presidio Ospedaliero A.Perrino - Divisione di Ematologia	Brindisi
Italy	Divisione di Ematologia Osp. Businco	Cagliari
Italy	IRCC Onco-Ematologia	Candiolo
Italy	Ospedale Ferrarotto	Catania
Italy	Policlinico Careggi Clinica Ematologica	Firenze
Italy	A.O.U. San Martino	Genova	GE
Italy	A O Papardo	Messina
Italy	A.O. Niguarda	Milano	MI
Italy	Ematologia e Trapianto IRCCS, Istituto Nazionale dei Tumori	Milano
Italy	IRCCS San Raffaele Unità di Chemioterapia	Milano
Italy	Policlinico di Modena - Università degli studi	Modena
Italy	Ematologia, A.O. San Gerardo	Monza	Milano
Italy	Istituto Pascale Oncoematologia	Napoli
Italy	SCDU Ematologia - Università del Piemonte Orientale	Novara
Italy	Ospedale S. Francesco	Nuoro
Italy	Presidio Ospedaliero "A. Tortora"	Pagani	SA
Italy	Azienda Ospedaliera V. Cervello	Palermo
Italy	U.O. Complessa di Ematologia Ospedale di Parma	Parma
Italy	Ematologia Policlinico San Matteo	Pavia
Italy	Ospedale Santa Maria della Misericordia	Perugia
Italy	Ospedale Santo Spirito Dipartimento di Ematologia	Pescara
Italy	Unità Ematologia Ospedale Civile di Piacenza	Piacenza
Italy	Ausl Ravenna	Ravenna
Italy	Azienda Ospedaliera "Bianchi Melacrino Morelli"	Reggio Calabria	RC
Italy	SC Ematologia AO Santa Maria Nuova IRCCS	Reggio Emilia
Italy	IRCCS-Centro di riferimento oncologico UO di ematologia e Trapianto Cellule Staminali	Rionero in Vulture	Potenza
Italy	Univeristà La Sapienza	Roma
Italy	Emat Univ - Città della salute e della scienza di Torino	Torino	TO
Italy	SC Ematologia Città della salute e della scienza di Torino	Torino
Italy	Filippo Gherlizoni	Treviso
Italy	UO Ematologia Osp. Cardinale Panico	Tricase
Italy	Clinica di Ematologia - A.O.U. S. Maria di Udine	Udine
Italy	Ospedale Policlinico G.B. Rossi (Borgo Roma) Di Verona	Verona	VR
Italy	Ospedale San Bortolo	Vicenza	VI

Sponsors (1)

Lead Sponsor	Collaborator
Fondazione Italiana Linfomi - ETS

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	36 months
Secondary	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.	36 months
Secondary	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).	36 months
Secondary	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.	36 months
Secondary	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.	42 months
Secondary	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	42 months
Secondary	Complete Response (CR) Rate	Proportion of CR according to the Cheson 2007 response criteria at the end of consolidation phase.	At the end of the consolidation phase (6 months)
Secondary	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.	At the end of the consolidation phase (6 months)
Secondary	Toxicity	Incidence of grade 3 or higher Toxicity measured by CTCAE v.4.03 during therapy.	42 months
Secondary	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.	36 months
Secondary	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.	6 months
Secondary	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.	24 months