Table 2.
Active agents and combinations in clinical trial history for BTKi-resistant MCL
| Drug or combination | Target inhibitor | Study (N) | Outcomes | Adverse events | CT identifier (Ref) |
|---|---|---|---|---|---|
| MK-1026 | BTKi | R/R Phase 1 (6) | ORR 57.9% | Fatigue (33%), constipation (31%), dysgeusia (28%), cough (25%), nausea (25%), pyrexia (25%), dizziness (23%), hypertension (23%), peripheral edema (22%), diarrhea (21%), and arthralgia (20%) | NCT03162536 |
| Bortezomib | Proteosome | R/R Phase 2 (155) | DOR 9.2 months OS 13.4 months | Grade 3 neuropathy, Thrombocytopenia | NCT00063713 [53] |
| Venetoclax | BCL2 | R/R Phase 1 (28) |
ORR 67% PFS 11.3 months DOR 15.7 months |
Neutropenia (19%), anemia (17%), and thrombocytopenia (15%) | NCT01328626 [54] |
| Ibrutinib + Venetoclax |
BTKi BCL2 |
R/R Phase 2 (24) |
PFS 29 months OS 32 months |
Infections, Grade 1-2 nausea, and diarrhea | NCT02471391 |
| Idelalisib | PI3Kδ | R/R Phase 1 (40) |
ORR 40% DOR 2.7 months |
Diarrhea (40.0%), nausea (32.5%), pyrexia (27.5%), fatigue (25%), rash (22.5%), | NCT00710528 [55] |
| Parsaclisib | PI3Kδ | R/R Phase 2 (108) |
ORR 70% DOR 13.7 months PFS 11.99 months |
Diarrhea (34.3%), pyrexia (17.6%), and constipation (13.0%) | NCT03235544 |
| Idelalisib | PI3Kδ | Phase 1 (40) |
ORR 40% CR 5% PR 35% |
Diarrhea (40.0%), nausea (32.5%), pyrexia (27.5%), fatigue (25%), rash (22.5%) | NCT00710528 [55] |
| Lenalidomide | Immune Modulator | R/R Phase 2 (134) |
ORR 28% DOR 16.6 months PFS 4 months OS 19 months |
Neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%) | NCT00737529 [56] |
| Lenalidomide vs (cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil) SPRINT | Immune modulator | R/R Phase 2 (254) |
ORR 68% D0R 16.8 months |
Neutropenia 44%, thrombocytopenia 18% | NCT00875667 [57] |
| Lenalidomide | Immune modulator | R/R Phase 2 (58) |
ORR 29% CR 14% DOR 20 months |
Peripheral edema 19% Fatigue 38% | NCT02341781 [58] |
| Pembrolizumab | Immune checkpoint inhibitor | Phase 1/2 (12) |
ORR 25% CR 8.3% PR 16% |
Grade 3 neutropenia | NCT02650999 [59] |
| Varlilumab (CDX-1127) | CD27mAb | Phase 1 (35) | 78% shrinkage of target lesions | Grade 1–2 fatigue, rash, nausea, and diarrhea | NCT01460134 |
| Daratumumab | CD38 mAb | Phase 2 (5) |
ORR 6.7%, CR 13.3% |
Cough, dyspnea, nausea, fatigue, anemia, Grade 3-4 neutropenia, and thrombocytopenia | NCT02413489 [60] |
| Vorinostat and Bortezomib | HDAC inhibitor + Proteasomal Inhibitor | Phase 1 (65) |
PFS 7.6 months ORR 27% |
Neutropenia and thrombocytopenia, Grade 3 gastrointestinal toxicity | NCT00703664 [61] |
| Vorinostat combined with RICE chemotherapy | HDAC | R/R Phase 1/2 (5) | ORR 60% | Grade 3 gastrointestinal toxicity, infection, hypokalemia, transaminitis | NCT00601718 |
| Abexinostat | HDAC | R/R Phase 1/2 (11) | ORR 27.3% PFS 3.9 months | Grade 3 neutropenia and thrombocytopenia | NCT03939182 [62] |
| Palbociclib | |||||
| (PD-0332991) | CDK4/6 | R/R Phase 1 (17) |
ORR 18% PFS > 1 year |
Grade 3–4 neutropenia and thrombocytopenia | NCT00420056 [63] |
| Palbociclib + Bortezomib | CDK4/6 + Proteasome | R/R Phase 1 (19) | ORR 27% | Neutropenia (63%) and thrombocytopenia (53%) | NCT01111188 [64] |
| Palbociclib + Ibrutinib | CDK4/6 + BTKi | R/R Phase 1 (27) |
ORR 67% CDR 37%, 2-year PFS 59% |
Neutropenia (41%) and thrombocytopenia (30% | NCT02159755 [65] |
| Abemaciclib | CDK | R/R Phase 1 (22) | ORR 23% | Neutropenia (32% grade ≥ 3), thrombocytopenia (32% grade ≥ 3), diarrhea (55%) | NCT01739309 |
| AT7519M | CDK | R/R Phase 1 (12) | ORR 27% | Grade 3 gastrointestinal toxicity | NCT01652144 |
| Flavopiridol | CDK | R/R Phase 1 (30) | ORR 11% | 1 MCL patient with Grade 3 tumor lysis syndrome | NCT00058227 |
| Everolimus (RAD001) | mTOR | Phase 2 (58) |
ORR 8.6%, CR 0% |
Anemia (20.7%), Thrombocytopenia (6.9%), Diarrhea (60.3%), Nausea (27.6%) | NCT00702052 [66] |
| VcR-CAP and R-CHOP (LYM-3002 trial) | Combination of BTKi | R/R Phase 3 (487) | ORR 64% | Grade 2 neutropenia and thrombocytopenia | NCT00722137 [67] |
| Venetoclax + Ibrutinib (AIM) |
BCL2 + BTKi |
R/R Phase 2 (23) | ORR 71% | Neutropenia and thrombocytopenia | NCT02471391 |
| Venetoclax + ibrutinib (SYMPATICO) |
BCL2 + BTKi |
R/R Phase 3 (352) |
ORR 81% CR 31% |
Diarrhea 83%, fatigue 75%, and nausea 71% | NCT03112174 [68] |
| ABT-199 + Ibrutinib |
BCL2 + BTKi |
R/R Phase 1 (37) |
ORR 83% CR 42% |
Grade 4 neutropenia, Grade 3 diarrhea, Grade 3 respiratory disorder | NCT02419560 [69] |
| Rituximab + Ibrutinib | CD20 mAb + BTKi | R/R Phase 2 (113) |
ORR 88% CR 44% |
Atrial fibrillation 10% | NCT01880567 [70] |
| Obinutuzumab (GUAGIN) | CD20 mAb | R/R Phase 2 (15) | ORR 27% | Infusion-related reactions (73%) | NCT00517530 [71] |
| Obinutuzumab + Ibrutinib (OAsIs) | CD20 mAb + BTKi | Chemo naive + R/R Phase 1/2 (48) |
CR 67% (Chemo naive) CR 86.6 (R/R) > 2 year PFS (69.5%) |
Grade 3 thrombocytopenia and neutropenia | NCT02558816 [72] |
| Selinexor + Ibrutinib | Exportin-1 (XPO1) + BTKi | Phase 1 (3) | ORR 32% | Fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) | NCT02303392 [73] |
ORR overall response rate, PFS progression-free survival, CR complete response, PR partial response, DOR duration of response, CT clinical trial