TY - JOUR
T1 - Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial
AU - Di Giacomo, Anna Maria
AU - Covre, Alessia
AU - Finotello, Francesca
AU - Rieder, Dietmar
AU - Danielli, Riccardo
AU - Sigalotti, Luca
AU - Giannarelli, Diana
AU - Petitprez, Florent
AU - Lacroix, Laetitia
AU - Valente, Monica
AU - Cutaia, Ornella
AU - Fazio, Carolina
AU - Amato, Giovanni
AU - Lazzeri, Andrea
AU - Monterisi, Santa
AU - Miracco, Clelia
AU - Coral, Sandra
AU - Anichini, Andrea
AU - Bock, Christoph
AU - Nemc, Amelie
AU - Oganesian, Aram
AU - Lowder, James
AU - Azab, Mohammad
AU - Fridman, Wolf H
AU - Sautès-Fridman, Catherine
AU - Trajanoski, Zlatko
AU - Maio, Michele
PY - 2019/12/15
Y1 - 2019/12/15
N2 - PURPOSE: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. PATIENTS AND METHODS: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m(2)/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics. RESULTS: Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n = 8) at week 4 (74.5%) and week 12 (75.5%) was significantly (P <0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P <0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8(+), PD-1(+) T cells and in CD20(+) B cells in posttreatment tumor cores. CONCLUSIONS: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.
AB - PURPOSE: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. PATIENTS AND METHODS: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m(2)/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics. RESULTS: Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n = 8) at week 4 (74.5%) and week 12 (75.5%) was significantly (P <0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P <0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8(+), PD-1(+) T cells and in CD20(+) B cells in posttreatment tumor cores. CONCLUSIONS: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.
U2 - 10.1158/1078-0432.CCR-19-1335
DO - 10.1158/1078-0432.CCR-19-1335
M3 - Article
VL - 25
SP - 7351
EP - 7362
JO - Clin. Cancer Res.
JF - Clin. Cancer Res.
SN - 1078-0432
IS - 24
ER -