Table 2.
Clinical trials with targeted BCR inhibition in combinatorial treatments.
| Targets | Drug/Regimen | Clinical Trial | Phase | Nb Pts | Status | Conditions | Response Data | References |
|---|---|---|---|---|---|---|---|---|
| BTK PD1 |
Acalabrutinib + Pembrolizumab | NCT02362035 | 1 & 2 | 161 | Active | R/R DLBCL | ORR 26% Discontinuation was due to PD (62%) and AEs (26%) |
[153] |
| BTK | Acalabrutinib + R-CHOP | NCT03571308 | 1 & 2 | 39 | Active | nHL | NA | NA |
| BTK | Ibrutinib + R-CHOP | NCT01855750 | 3 | 838 | Completed | B-cell Lymphomas | ORR 93.6% | [154] |
| BTK | Ibrutinib + R-ICE | NCT02219737 | 1 | 26 | Completed | DLBCL | ORR 90% | [155] |
| BTK | Ibrutinib + CAR-T cell | NCT05020392 | 3 | 24 | Active | DLBCL, MCL, CLL, SLL, BL | ORR 83% | [156] |
| BTK PDL1 4-1BB CD20 |
Ibrutinib + Avelumab + Utomilumab + Rituximab | NCT03440567 | 1 | 16 | Active | R/R DLBCL, R/R MCL, Transformed FL | NA | NA |
| BTK | Ibrutinib + Immuno-chemotherapy | NCT02055924 | 1 | 85 | Terminated | B-cell Lymphomas | CR 42% PR 25% Terminated due to due to veno occlusive disease |
[157] |
| BTK JAK1 | Ibrutinib + Itacitinib | NCT02760485 | 1 & 2 | 33 | Active | B-cell Lymphomas | ORR 24% | [158] |
| BTK | Ibrutinib + Lenalidomide | NCT01955499 | 1 | 34 | Active | R/R DLBCL, R/R FL, R/R MZL, R/R MCL | NA | NA |
| BTK CD20 |
Ibrutinib + Rituximab | NCT01980654 | 2 | 80 | Completed | B-cell Lymphomas | ORR 85–75% | [159] |
| BTK CD20 |
Ibrutinib + Rituximab + Bendamustine | NCT01479842 | 1 | 48 | Active | MZL, FL, MCL, WM | OR 94% in MCL and 37% in DLBCL CR 76% in MCL and 31% in DLBCL | [160] |
| BTK | Ibrutinib + Rituximab + Lenalidomide | NCT02636322 | 2 | 60 | Active | DLBCL | ORR 65% DOR 15.9 months |
[161] |
| BTK CD20 |
Ibrutinib + Rituximab + Lenalidomide | NCT02077166 | 1 & 2 | 134 | Completed | R/R DLBCL | ORR 47% CR 28% PFS 21 months AEs grade > 3 in less 30% patients |
[162] |
| BTK CD20 |
Ibrutinib + Rituximab + Venetoclax | NCT03136497 | 1 | 10 | Active | R/R DLBCL | NA | NA |
| BTK | Spebrutinib | NCT01351935 | 1 | 113 | Completed | B-cell Lymphomas | ORR 53% | [163] |
| BTK | Spebrutinib + Lenalidomide | NCT01766583 | 1 | 18 | Completed | R/R B-cell Lymphomas | NA | NA |
| BTK CD20 |
Zanubrutinib + Rituximab | NCT03520920 | 2 | 41 | Completed | MZL, FL, DLBCL | ORR 35% PFS 3.38 months |
[164] |
| BTK mTOR |
DTRMWXHS-12 + Everolimus + Pomalidomide | NCT02900716 | 1 | 48 | Completed | B-cell Lymphomas | Well-tolerated and no DLT achieved | [131] |
| BTK PI3K |
Ibrutinib + Umbralisib | NCT02874404 | 2 | 13 | Completed | R/R DLBCL | ORR 31% PFS 3 months |
[165] |
| BTK PI3K CD20 |
Ibrutinib + Parsaclisib+ Rituximab+ Bendamustine | NCT03424122 | 1 | 50 | Active | B-cell Lymphomas | NA | NA |
| BTK PI3K | Ibrutinib + Umbralisib | NCT02268851 | 1 | 45 | Active | CLL, SLL, MCL | ORR 67% CR 19% PR 48% AEs grade >3 in less than 10% |
[166] |
| BTK PI3K CD20 |
Ibrutinib + Umbralisib + Ublituximab + Bendamustine | NCT02006485 | 1 | 160 | Completed | B-cell Lymphomas | DOR 20 months | [167] |
| mTOR | Everolimus + Lenalidomide | NCT01075321 | 1 & 2 | 58 | Completed | MZL, FL, MCL, WM | ORR 27% | [168] |
| mTOR | Everolimus + Panobinostat | NCT00962507 | 1 | 11 | Completed | B-cell Lymphomas | ORR 43% CR 15% |
[169] |
| mTOR | Everolimus + Panobinostat | NCT00978432 | 2 | 50 | Terminated | DLBCL | Terminated due to toxicities, which seemed to outweigh the benefits | [170] |
| mTOR | Everolimus + Panobinostat | NCT00918333 | 1 & 2 | 124 | Completed | MZL, BL, MCL, SLL, CLL, ALL, WM | NA | NA |
| mTOR CD20 |
Everolimus + Rituximab | NCT00869999 | 2 | 26 | Completed | DLBCL | OR 38% SD 8% DOR 8.1 months |
[171] |
| mTOR | Everolimus + Sorafenib | NCT00474929 | 1 & 2 | 103 | Completed | B-cell Lymphomas | ORR 30% in DLBCL and 38% in MCL DOR 5.7 months |
[172] |
| mTOR | Everolimus + Sotrastaurin | NCT01854606 | 1 | 31 | Completed | ABC DLBCL | Due to suboptimal tolerability of the combinations the phase II is not conducted | NA |
| mTOR | Sirolimus + hyperCVAD | NCT01184885 | Early 1 | 7 | Completed | ALL, BL, MCL NA | NA | NA |
| mTOR CD22 |
Temsirolimus + Inotuzumab oxogamicin | NCT01535989 | 1 | 25 | Completed | R/R B-cell Lymphomas | PR 39% This drug combination is not possible due to toxicities |
[173] |
| PI3K CD20 |
Buparlisib + Rituximab | NCT02049541 | 1 | 18 | Active | R/R FL, R/R MZL, R/R MCL, WM | NA | NA |
| PI3K SYK |
Idelalisib + Entospletinib | NCT01796470 | 2 | 66 | Terminated | B-cell Lymphomas | Terminated due to pneumonitis in 18% of patients | [174] |
| SYK | TAK-659 + R-CHOP | NCT03742258 | 1 | 12 | Active | DLBCL | NA | NA |
Abbreviations: FL, follicular lymphoma; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; WM, waldenstrom’s macroglobulinemia; ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; DOR, duration of response; PFS, progression-free survival; OS, overall survival; AEs, adverse effects; NA, not available.