Background: Bevacizumab (B) is effective in metastatic Renal Cell Cancer (mRCC) and has a synergistic effect with Chemotherapy (Ch) in many tumors. The activity of B plus immunotherapy (It) with interleukin- 2 (IL-2) and interferon-α (IFN-α) has not been studied. Our previous dose-finding study showed the feasibility of the combination B+It+Ch (BIC regimen) [JCO Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 15586]. Aim of this study is to explore the efficacy of BIC and to correlate its efficacy with the variations in circulating T regulatory lymphocytes (Treg). Methods: Patients (pts) with histological diagnosis of mRCC, previous nephrectomy, PS 0-1, adequate organ function, no untreated CNS metastases and 0-2 previous systemic regimens were treated with B (10 mg/kg days 1 and 15) plus Ch (Gemcitabine: 1,000 mg/m2 i.v. in 1 hour followed by 5-fluorouracil 600 mg/m2 iv bolus days 1 and 8 every 28) plus It (IL-2: 1 MUI/m2 bid sc days 8, 9, 15, 16 and 1 MUI/m2/die sc from day 10 to 12 and from 17 to 19; and IFN-α: 3 MUI sc on days 10, 12, 17, 19). This phase II study was conducted according to two stages Minimax Simon design. CT was repeated for a maximum of 6 cycles followed by maintenance with B and It until progressive disease (PD). In 30 pts, blood samples for Treg were evaluated on days: 1, 8, 15, 22, 29 of cycle 1 and at the disease progression (PD). Recist criteria and ITT analysis were applied. Results: 45 pts were included: male 66%; median age 59 years; 47% pre-treated; 18% PS ≥ 1; 43 pts were evaluable for response (2 too early) and we observed 33% partial response (PR), 31% stable disease (SD) and 31% PD for an overall disease control rate (DCR) of 64%. Median PR/SD duration was 7.3 months (mths). Median TTP was 8.2 mths (95% CI: 6.9-9.4). In 24 not pre-treated pts DCR was 79%. In MSKCC poor risk group (13%) we observed 33% PR and a DCR of 83% with a TTP of 8.7 mths. Treatment was well tolerated, grade 3-4 toxicity included neutropenia non-febrile 36%, febrile 2%, thrombocytopenia 27%, flu-like syndrome 19%, hypertension 7%. Data show overall increased percentage of Treg, identified by FACS analysis as CD4+/CD25high/FoxP3+ in PBMCs, after the first week of It (day 15) and a overall decrease after the treatment with B (day 22); but from day 15 to 22 in PR/SD pts Treg decrease, while PD pts Treg increase. Conclusions: BIC combination is effective in all subgroups of mRCC and is well tolerated. Variation in Treg during first cycle seems to be correlated with the response to treatment

Combination of Bevacizumab plus low-doses Immunotherapy plus Chemotherapy (BIC regimen) in metastatic renal cell cancer: antitumor effects and variations of T-regulatory cells (Treg) during the treatment. A multicentre study of the Italian Oncology Group for Clinical Research (GOIRC) / Buti, S; Lazzarelli, S; Simonelli, C; Lo Re, G; Lleshi, A; Mattioli, R; Passalacqua, R. - (2008). (Intervento presentato al convegno Second Pavia International Symposium on Advanced Kidney Cancer tenutosi a Pavia nel 26-27 June, 2009).

Combination of Bevacizumab plus low-doses Immunotherapy plus Chemotherapy (BIC regimen) in metastatic renal cell cancer: antitumor effects and variations of T-regulatory cells (Treg) during the treatment. A multicentre study of the Italian Oncology Group for Clinical Research (GOIRC)

Buti S;
2008-01-01

Abstract

Background: Bevacizumab (B) is effective in metastatic Renal Cell Cancer (mRCC) and has a synergistic effect with Chemotherapy (Ch) in many tumors. The activity of B plus immunotherapy (It) with interleukin- 2 (IL-2) and interferon-α (IFN-α) has not been studied. Our previous dose-finding study showed the feasibility of the combination B+It+Ch (BIC regimen) [JCO Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 15586]. Aim of this study is to explore the efficacy of BIC and to correlate its efficacy with the variations in circulating T regulatory lymphocytes (Treg). Methods: Patients (pts) with histological diagnosis of mRCC, previous nephrectomy, PS 0-1, adequate organ function, no untreated CNS metastases and 0-2 previous systemic regimens were treated with B (10 mg/kg days 1 and 15) plus Ch (Gemcitabine: 1,000 mg/m2 i.v. in 1 hour followed by 5-fluorouracil 600 mg/m2 iv bolus days 1 and 8 every 28) plus It (IL-2: 1 MUI/m2 bid sc days 8, 9, 15, 16 and 1 MUI/m2/die sc from day 10 to 12 and from 17 to 19; and IFN-α: 3 MUI sc on days 10, 12, 17, 19). This phase II study was conducted according to two stages Minimax Simon design. CT was repeated for a maximum of 6 cycles followed by maintenance with B and It until progressive disease (PD). In 30 pts, blood samples for Treg were evaluated on days: 1, 8, 15, 22, 29 of cycle 1 and at the disease progression (PD). Recist criteria and ITT analysis were applied. Results: 45 pts were included: male 66%; median age 59 years; 47% pre-treated; 18% PS ≥ 1; 43 pts were evaluable for response (2 too early) and we observed 33% partial response (PR), 31% stable disease (SD) and 31% PD for an overall disease control rate (DCR) of 64%. Median PR/SD duration was 7.3 months (mths). Median TTP was 8.2 mths (95% CI: 6.9-9.4). In 24 not pre-treated pts DCR was 79%. In MSKCC poor risk group (13%) we observed 33% PR and a DCR of 83% with a TTP of 8.7 mths. Treatment was well tolerated, grade 3-4 toxicity included neutropenia non-febrile 36%, febrile 2%, thrombocytopenia 27%, flu-like syndrome 19%, hypertension 7%. Data show overall increased percentage of Treg, identified by FACS analysis as CD4+/CD25high/FoxP3+ in PBMCs, after the first week of It (day 15) and a overall decrease after the treatment with B (day 22); but from day 15 to 22 in PR/SD pts Treg decrease, while PD pts Treg increase. Conclusions: BIC combination is effective in all subgroups of mRCC and is well tolerated. Variation in Treg during first cycle seems to be correlated with the response to treatment
2008
Combination of Bevacizumab plus low-doses Immunotherapy plus Chemotherapy (BIC regimen) in metastatic renal cell cancer: antitumor effects and variations of T-regulatory cells (Treg) during the treatment. A multicentre study of the Italian Oncology Group for Clinical Research (GOIRC) / Buti, S; Lazzarelli, S; Simonelli, C; Lo Re, G; Lleshi, A; Mattioli, R; Passalacqua, R. - (2008). (Intervento presentato al convegno Second Pavia International Symposium on Advanced Kidney Cancer tenutosi a Pavia nel 26-27 June, 2009).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2906846
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