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

Study Overview
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Brief Summary
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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
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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)

Official Title
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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

Conditions
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Relapsed Follicular Lymphoma

Intervention / Treatment
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* Other: ZEVALIN
* Drug: BEAM


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A RIT<br>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<br>* 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).<br>* Other names: RIT;|
| Experimental: ARM B ASCT<br>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<br>* 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<br>* Other names: ASCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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) | 
| Toxicity | Incidence of grade 3 or higher Toxicity measured by CTCAE v.4.03 during therapy. | 42 months | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed follicular Lymphoma, RIT, Zevalin