The phase I part (safety assessment of the combination treatment) is aimed at determining the MTD of atezolizumab when combined with BEGEV schedule. 6-18 patients enrolled in this part will be treated with atezolizumab in combination with BEGEV regimen every 3 weeks for 4 cycles. Patients without a DLT in the first cycle and without disease progression after cycle 2, will undergo stem cell mobilization with 3-4 cycle of A-BEGEV + granulocyte colony-stimulating factor (G-CSF) and subsequently receive a myeloablative therapy followed by ASCT. The phase IIb part (expansion cohort) plans to randomize 122 patients in two arms (A and B, 61 per arm): 1. arm A will receive the BEGEV regimen followed by ASCT for patients achieving CR. 2. arm B will receive combination treatment with Atezolizumab and BEGEV regimen followed for patients reaching CR by ASCT plus a consolidation with 6 doses of atezolizumab at 1200 mg every 4 weeks. After the last treatment date of the last patient (LPLT), the phase IIb will be ended. A long term follow up will start, in order to better assess patients' prognosis. All evaluable patients from phase I and phase IIb study will enter in the long term follow up phase and will be followed for 18 months.
The phase I part (safety assessment of the combination treatment) is aimed at determining the MTD of atezolizumab when combined with BEGEV schedule. 6-18 patients enrolled in this phase will be treated with atezolizumab in combination with BEGEV regimen every 3 weeks for 4 cycles. Patients without a DLT in the first cycle and without disease progression after cycle 2, will undergo stem cell mobilization with 3-4 cycle of A-BEGEV + granulocyte colony-stimulating factor (G-CSF) and subsequently receive a myeloablative therapy followed by ASCT. Patients with documented CR following ASCT will receive a consolidation therapy with atezolizumab as single agent every 4 weeks for 6 doses, starting preferably between 60 and 90 days, but ≥ 60 days and not \> 120 days after autografting. In patients not previously radiotreated, adjuvant radiotherapy (RT) should be planned during consolidation treatment within the start of second consolidation dose, according to clinician's judgment and response assessment. RT will be administered at 30-36 Gy on sites of initial bulky disease or on single PET positive residual site. Patients reaching PR after four cycles of atezolizumab combined with BEGEV or with documented PR after ASCT may continue the study protocol according to the physician judgment. Dosing starts at 1200 mg and decreases in the successive cohort to the dose of 840 mg and 600 mg, according to Flow chart A. in the section 6 of the protocol. In the consolidation phase atezolizumab will be administered at dose of 1200 mg every 4 weeks for 6 doses without dose reduction, but only delay or discontinuation. Patients included in the cohort developing DLT, withdraw the protocol due to toxicity and continue the treatment according to good clinical practice. For patients included in the cohort of MTD, monitoring and collection of AEs will be continuous during induction, consolidation treatment and follow-up. The phase IIb part (expansion cohort) plans to randomize 122 patients in two arms (A and B, 61 per arm): 1. arm A will receive the BEGEV regimen followed by ASCT for patients achieving CR. 2. arm B will receive combination treatment with Atezolizumab and BEGEV regimen followed for patients reaching CR by ASCT plus a consolidation with 6 doses of atezolizumab at 1200 mg every 4 weeks. In patients not previously radiotreated, adjuvant RT should be planned for both patients in arm A and arm B according to clinician's judgment and response assessment. RT will be administered at 30-36 Gy on sites of initial bulky disease or on single PET positive residual site. Patients reaching PR after four induction cycles (atezolizumab combined with BEGEV or BEGEV alone) or with documented PR after ASCT may continue the study protocol according to the physician judgment. After the last treatment date of the last patient (LPLT), the phase IIb will be ended. A long term follow up will start, in order to better assess patients' prognosis. All evaluable patients from phase I and phase IIb study will enter in the long term follow up phase and will be followed for 18 months. Disease status, survival outcome, secondary primary malignancies and late toxicity will be collected every 6 months until patient withdrawal of consent, lost to follow up and patient's death. Long term follow-up phase will end 18 months after the end of phase IIb.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
122
In phase I study: Atezolizumab will be administered until the determination of its MTD when combined with BEGEV schedule. In phase II b study - arm A (standard): Atezolizumab will not be administered. In phase II b study - arm B (experimental): Atezolizumab will be administered at MTD determined in phase I study plus BEGEV regimen (at dosages performed by local practice).
In phase I study: Atezolizumab will be administered until the determination of its MTD when combined with BEGEV schedule. In phase II b study - arm A (standard): only BEGEV will be administered. In phase II b study - arm B (experimental): BEGEV regimen will be administered in combination with Atezolizumab at MTD determined in phase I.
S.C. Ematologia - A.O. SS. Antonio e Biagio e Cesare Arrigo
Alessandria, Alessandria, Italy
RECRUITINGEmatologia - Fondazione del Piemonte per l'Oncologia - IRCCS
Candiolo, Turin, Italy
RECRUITINGS.C. Ematologia e Trapianto emopoietico - Azienda Ospedaliera S.Giuseppe Moscati
Avellino, Italy
RECRUITINGDivisione di Oncologia e dei Tumori immuto-correlati - IRCCS Centro di Riferimento Oncologico di Aviano
Aviano, Italy
For Phase I part: evaluation of the maximum tolerated dose (MTD) of the atezolizumab.
The maximum tolerated dose (MTD) of the atezolizumab in combination with BEGEV will be established in the first cycle of therapy, in order to determine the recommended phase II dose (RP2D). Patients will be accrued in 3 patients cohorts at each dose level, starting from level 1. Dose de-escalation will be performed following the standard 3+3 rule, registering any Dose Limiting Toxicity (DLT).
Time frame: During first cycle of treatment based on atezolizumab in combination with BEGEV in phase I study. Maximum time frame 17 months.
For Phase II part: evaluation of the Complete Response Rate (CRR) before ASCT.
The assessment of CRR before ASCT will be performed by an independent radiologic review committee (IRRC) according to the Lugano classification response criteria (2014) and the LYmphoma Response to Immunomodulatory Therapy Criteria (LYRIC 2016). CRR will be defined as the proportion of patients in CR after the first 4 cycles of induction treatment, according to Lugano classification response Criteria and LYRIC 2016 criteria. Patients without response assessment (due to whatever reason) will be considered as non-responders.
Time frame: From initial treatment based on Atezolizumab and BEGEV to intensification treatment with ASCT. Time frame 4 months.
For Phase II part: evaluation of the overall response rate (ORR), partial response (PR), stable disease (SD) and progression disease (PD) rates.
The assessment of the overall response rate (ORR), partial response (PR), stable disease (SD) and progression disease (PD) rates will be performed according to the Lugano 2014 criteria and LYRIC 2016 criteria.
Time frame: The best response between the date of beginning of therapy and the last restaging. Time frame 14 months.
For Phase II part: evaluation of the rate of partial response (PR) converted to Complete Response (CR).
The rate of PR converted to CR will be assessed as the number of PR converted in CR at the end of consolidation treatment with atezolizumab in the experimental arm.
Time frame: At the end of consolidation treatment with atezolizumab in the experimental arm. Time Frame 14 months.
For Phase II part: evaluation of the peripheral blood stem-cell mobilization
The peripheral blood stem-cell mobilization will be assessed in patients receiving atezolizumab combined to BEGEV schedule. Adequate stem cells mobilization will be defined by the target cell harvesting of 3 x 1.000.000 CD34+ cells/kg.
Time frame: At the end of treatment based on atezolizumab and BEGEV. Time Frame 3 months.
For Phase II part: evaluation of engraftment after ASCT
Engraftment will be assessed in patients who received ASCT after salvage treatment with atezolizumab combined to BEGEV. Engraftment will be defined as the first of three consecutive days of achieving a sustained peripheral blood neutrophil count of \>500 × 1.000.000/L. Platelet engraftment is usually defined as independence from platelet transfusion for at least 7 days with a platelet count of more than \>20 × 1.000.000.000/L.
Time frame: Between 30 and 60 days after ASCT: Time Frame 5 months.
For Phase II part: evaluation of duration of response (DoR).
The duration of response will be defined as the time from date of documented tumor response (CR) until lymphoma relapse or progression.
Time frame: From the CR to the date of relapse or progression or last scheduled visit. Time frame 50 months.
For Phase II part: evaluation of Progression Free Survival (PFS) for all patients.
PFS will be assessed for all patients and it will be defined as the time from beginning of therapy until lymphoma relapse or progression or death as a result of any cause; responding patients and patients who are lost to follow up will be censored at their last assessment date. It will be measured also in long-tem follow up in order to better assess patients' prognosis.
Time frame: From beginning therapy to progression or relapse disease or death. Time frame 50 months.
For Phase II part: evaluation of OS.
OS will be assessed for all patients and it will be defined as the time from beginning of therapy until death as a result of any cause; alive patients and those who are lost to follow up will be censored at their last assessment date. it will be measured also in long-tem follow up in order to better assess patients' prognosis.
Time frame: From the beginning of therapy to death for any cause or last scheduled visit. Time frame 50 months.
For Phase II part: evaluation of safety and tolerability of atezolizumab and BEGEV.
The safety and the tolerability of a first salvage treatment based on the combination of intravenous (IV) atezolizumab and BEGEV regimen will be assessed throughout the study by the measurement of: patients' withdrawal rate, incidence, type and grade of any adverse event (AE) and serious adverse event (SAE) assessed by CTCAE v.4.0, hospitalization rate (except it for study therapy administration).
Time frame: From the beginning of treatment to death or lost to follow-up or last scheduled visit. Time frame 50 months.
For Phase II part: evaluation of he correlation of quantitative baseline PET parameters
To evaluate the correlation of quantitative baseline PET parameters with progression/failure free survival and overall survival.
Time frame: From the beginning of treatment to death or lost to follow-up or last scheduled visit. Time frame 50 months.
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U.O.C Ematologia - IRCCS Istituto Tumori Giovanni Paolo II
Bari, Italy
RECRUITINGEmatologia - Ospedale "Monsignor Raffaele Dimiccoli"
Barletta, Italy
NOT_YET_RECRUITINGEmatologia - ASST Spedali Civili di Brescia
Brescia, Italy
RECRUITINGOspedale S. Maria Goretti - UOC Ematologia con Trapianto
Latina, Italy
NOT_YET_RECRUITINGEmatologia - Ospedale Vito Fazzi
Lecce, Italy
RECRUITINGIRCCS Istituto Romagnolo per lo studio dei Tumori "Dino Amadori" - IRST S.R.L. - Ematologia
Meldola, Italy
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