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

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)

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