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Table 2 Current status of clinical trials testing combinations of HMA (epigenetic priming) with strategies targeting checkpoint receptors/ligands

From: The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation

HMA (Synonym)
[Application Route]
Checkpoint Target (Synonym) Compound (Synonym)
[Application Route]
Status (design) Indication ClinicalTrials.gov identifier
Azacitidine (CC-486)
[p.o., 300 mg d1-15]
CD279 (PD1) Pembrolizumab (Lambrolizumab, MK-3475)
[i.v., 200 mg Q3W]
Phase II (non-randomized) Metastatic melanoma, other skin neoplasms NCT02816021
Azacitidine (CC-486)
[p.o., 300 mg d1-14, Q3W]
CD279 (PD1) Pembrolizumab (Lambrolizumab, MK-3475)
[i.v., 200 mg Q3W, d1]
Phase II (randomized)
• MK-3475 + CC-486
• MK-3475 + placebo
Previously treated locally advanced or metastatic NSCLC NCT02546986
Azacitidine [s.c., 100 mg d1-5, Q4W] CD279 (PD1) Pembrolizumab (Lambrolizumab, MK-3475)
[i.v., 200 mg Q3W]
Phase II (non-randomized) Chemo-refractory metastatic CRC NCT02260440
Azacitidine [s.c./i.v., 75 mg/m2 d1-7 Q4W] CD279 (PD1) Pembrolizumab (Lambrolizumab, MK-3475)
[200 mg i.v., Q3W, d8]
Phase II (non-randomized) Relapsed/refractory AML and newly diagnosed AML >65 years NCT02845297
Azacitidine (CC-486)
[p.o., 300 mg d1-14 or d1-21, Q4W]
CD279 (PD1) Pembrolizumab (Lambrolizumab, MK-3475)
[200 mg i.v., Q3W]
Phase II (randomized)
• CC-486 100 mg + MK-3475
• CC-486 100 mg BID + MK-3475
• CC-486 300 mg d1-14 + MK-3475
• CC-486 300 mg d1-21 + MK-3475
Platinum resistant ovarian, fallopian tube or primary peritoneal cancer NCT02900560
Azacitidine (CC-486)
[p.o., 300 mg d1-14 or d1-21, Q4W]
+/- Romidepsin (HDAC-I) [7 or 14 mg/m2, d1,8,15, Q4W]
CD279 (PD1) Pembrolizumab (Lambrolizumab, MK-3475)
[200 mg i.v., Q4W, d1 + 15]
Phase I (randomized)
• CC-486 + MK-3475
• Romidepsin + MK-3475
• CC-486 + Romidepsin + MK-3475
Microsatellite stable advanced CRC NCT02512172
Guadecitabine (SGI-110)
[s.c., d1-4, Q4W]
CD279 (PD1) Pembrolizumab (Lambrolizumab, MK-3475)
[200 mg i.v., Q4W, d5]
Phase II (non-randomized) Platinum resistant ovarian, fallopian tube or primary peritoneal cancer NCT02901899
Azacitidine
[s.c., 40 mg/m2, d1-6, d8-10, Q4W]
+/- Entinostat (HDAC-I) [p.o., 8 mg, d3 + 10, Q4W]
CD279 (PD1) Nivolumab (BMS-936558, MDX-1106)
[i.v., 3 mg/kg, Q2W]
Phase II (randomized, sequential)
• 2 cycles AZA + Romidepsin, followed by Nivolumab
• Nivolumab
Recurrent metastatic NSCLC NCT01928576
THU-decitabine
[p.o., 10 mg/kg/0.2 mg/kg, d1-2, Q1W]
CD279 (PD1) Nivolumab (BMS-936558, MDX-1106)
[i.v., 3 mg/kg, Q2W]
Phase II (randomized)
• 2 cycles AZA + Romidepsin, followed by Nivolumab
• Nivolumab
2nd line therapy for NSCLC NCT02664181
Azacitidine
[s.c./i.v., 75 mg/m2 d1-7 Q4W]
CD279 (PD1) Nivolumab (BMS-936558, MDX-1106)
[i.v., 3 mg/kg, Q4W, d1 + 14]
Phase II (non-randomized) Relapsed/refractory AML and newly diagnosed AML >65 years NCT02397720
Azacitidine
[s.c./i.v., 75 mg/m2 d1-7, Q4W]
Lirilimab (anti-KIR mAb) [d7, Q4W]
CD279 (PD1) Nivolumab (BMS-936558, MDX-1106)
[i.v., 3 mg/kg, Q4W, d7 + 21]
Phase II (non-randomized) High-risk MDS NCT02599649
Azacitidine
[s.c., 75 mg/m2 d1-5, Q4W]
CD279 (PD1)
CD152 (CTLA-4)
Nivolumab (BMS-936558, MDX-1106)
[i.v., 3 mg/kg, Q3W, d6]
Ipilimumab (BMS-73406, MDX-010)
[i.v., 3 mg/kg, Q3W, d6]
Phase II (non-randomized, parallel assignment)
• AZA + Nivolumab
• AZA + Ipilimumab
• AZA + Nivolumab + Ipilimumab
Previously untreated MDS NCT02530463
Decitabine
[d1-5, Q4W]
CD152 (CTLA-4) Ipilimumab (BMS-73406, MDX-010)
[i.v., 3 mg/kg, Q8W, d1]
Phase I (non-randomized) Relapsed/refractory post allo-HSCT MDS RAEB I/II or AML NCT02890329
SGI-110
[30 mg/m2, d1-5, Q3W]
CD152 (CTLA-4) Ipilimumab (BMS-73406, MDX-010)
[i.v., 3 mg/kg, Q3W]
Phase I (non-randomized) Unresectable or metastatic melanoma NCT02608437
Azacitidine
[s.c., 75 mg/m2, d1-7, Q4W]
CD152 (CTLA-4)
CD274 (PD-L1)
Tremelimumab (CP-675,206)
Durvalumab
(MEDI-4736)
Phase I (non-randomized)
• Tremelimumab + Ipilimumab
• AZA + Tremelimumab + Ipilimumab
MDS relapsed/refractory to HMA NCT02117219
Azacitidine (CC-486)
[p.o., 300 mg d1-14, Q4W]
CD274 (PD-L1) Durvalumab (MEDI-4736)
[i.v., 1500 mg, Q4W, d1]
Phase II (non-randomized) Microsatellite stable CRC, platinum-resistant ovarian cancer, ER+ and HER2- breast cancer NCT02811497
Azacitidine
[s.c., 75 mg/m2, d1-7, Q4W]
CD274 (PD-L1) Durvalumab (MEDI-4736)
[i.v., 1500 mg, Q4W, d1]
Phase II (randomized)
• AZA + Durvalumab
• AZA
Previously untreated high-risk MDS or AML >65 years ineligible for allo-SCT NCT02775903
Azacitidine (CC-486)
[p.o., 200 mg d1-21, Q4W]
CD274 (PD-L1) Durvalumab (MEDI-4736)
[i.v.]
Phase II (randomized)
• CC-486 + Durvalumab
• CC-486
MDS refractory to Azacitidine or Decitabine NCT02281084
Azacitidine
[s.c., 75 mg/m2, d1-7 or d1-5 + 8-9, Q4W]
CD274 (PD-L1) Azetolizumab (MPDL-3280A)
(RG7446)
[i.v., 840 mg, d1 + 22, Q4W]
Phase II (non-randomized) HMA naive or relapsed/refractory MDS NCT02508870
Azacitidine
[s.c. or i.v., 75 mg/m2, d1-7, Q4W]
CD274 (PD-L1) Avelumab (MSB-0010718C)
[i.v., 3 mg/kg, d1 = +14, Q4W]
Phase I/II (non-randomized) Relapsed/refractory AML NCT02953561