Current clinical trials of PROTAC therapeutics in hematological malignancies
| Trial/clinical trial number . | PROTAC . | Target protein . | E3 ligase . | Disease context . | Clinical trial phase . | Patients, n . | Cohort description . | Additional cohort data . | Safety data . | Efficacy data . | References . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| NX-2127-001 NCT04830137 | NX-2127 | BTK/Ikaros/Aiolos | Cereblon | B-cell malignancies | 1 | Total: 54 33 CLL/SLL DLBCL, 6 MCL, 7 MZL, 3 WM, 3 FL, 2 | Median age: 72.5 y F:M, 31.5%:68.5% Median prior therapies: 4 CLL cohort: Median age: 74 y F:M, 33.3%:66.7% Median prior therapies: 5 NHL cohort: Median age: 70 y F:M, 28.6%:71.4% Median prior therapies: 4 | CLL cohort Previous BTKi: 100% Previous pirtobrutinib: 27.3% Previous BTKi & BCL2i: 78.8% BCL2 mutation: 12.1% BTK mutation: 36.4% | DLTs: 2 AE Gr ≥3: Neutropenia: 38.3% Hypertension: 14.9% Anemia: 12.8% Thrombocytopenia: 6.4% COVID-19: 6.4% Atrial fibrillation: 6.4% Pneumonia: 6.4% Leucocytosis: 6.4% Sepsis: 4.3% Increased lymphocyte count: 4.3% Pruritis: 2.1% Dyspnea: 2.1% | CLL evaluable cohort (n = 27) ORR: 40.7% PR: 40.7% SD: 44.4% PD: 14.8% NHL evaluable cohort (n = 17): CR: 11.8% PR: 11.8% SD: 29.4% PD: 47.1% | 88 |
| NX-5948-301 NCT05131022 | NX-5948 | BTK | Cereblon | B-cell malignancies | 1 | Total 26: 7 CLL 7 DLBCL 5 MCL 3 MZL 1 FL 1 PCNSL 2 WM | Median age: 65 y F:M, 28.6%:71.4% Median prior therapies: 4 | CLL cohort: Median age: 64 y F:M 28.6%:71.4% Median prior therapies: 3 TP53 aberrancy: 33.3% BTK mutation (T474): 16.7% PLCG1/2 mutation: 33.3% BCL2 mutation: 33.3% NHL/WM cohort: Median age: 63 y F:M 31.6%:68.4% Median prior therapies: 5 TP53 aberrancy: 20% | No DLTs recorded No treatment-related AE led to discontinuation AE Gr >3: Neutropenia: 19.2% Thrombocytopenia: 7.7% COVID-19: 7.7% Pneumonia: 7.7% Anemia: 3.8% | CLL evaluable cohort (n = 7) 3 PR (42.8%) 2 SD (28.5%) 2 PD (28.5%) NHL evaluable cohort: (n = 19) 2 PMR 1 PR 2 SD 13 PD | 89 89 |
| BGB-16673-101 NCT05006716 NCT05294731 | BGB-16673 | BTK | Undisclosed | B-cell malignancies | 1 | Total: 50 24 CLL/SLL 7 MCL 3 MZL 6 WM 2 DLBCL 6 FL 2 RT | Median age: 70.5 y F:M, 34%:66% Median prior therapies: 4 | CLL cohort unmutated IGHV: 84.2%, TP53 aberrancy: 45.8% Complex CG: 40% Whole cohort: Previous BTKi: 80% Previous BCL2i: 56% BTK mutation present: 29.2% PLCG2 mutation present: 8.3% BCL2 mutation present: 44.4% | No DLTs recorded Any AE Gr ≥3: 38% Treatment-related AE Gr ≥3: 22% Deaths: 4% AE Gr ≥3: Contusion: 30% Diarrhea: 24% Fatigue: 20% Increased amylase: 16% Neutropenia: 16% Increased lipase: 14% Pyrexia: 14% Cough: 12% Headache: 10% Pneumonia: 6% COVID-19 pneumonia: 4% AEs of interest Any bleeding: 42% Any infection: 50% Atrial fibrillation: 0% | Total evaluable cohort (n = 28): ORR: 54% CR: 4% PR/PR-L: 50% MR: 4% SD: 18% PD: 18% Ceased: 7% CLL evaluable cohort: (n = 10) PR/PR-L: 70% SD: 20% Ceased: 10% MCL/MZL/WM evaluable cohort (n = 16) CR: 6.3% PR: 43.8% MR: 6.3% SD: 18.8% PD 18.8% Ceased: 6.3% DLBCL/RT (n = 2) PD: 100% | 90 |
| NCT04861779 | HSK29116 | BTK | Undisclosed | B-cell malignancies | 1 | NA | 91 | ||||
| NCT05780034 | AC0676 | BTK | Undisclosed | B-cell malignancies | 1 | NA | 92 | ||||
| NCT05753501 | ABBV-101 | BTK | Undisclosed | B-cell malignancies | 1 | NA | 93 | ||||
| KT333-TL-101 NCT05225584 | KT-333 | STAT3 | Undisclosed | NHL, CTCL, LGL-L, PTCL | 1 | Total: 29 1 B-cell NHL 1 HL 5 CTCL 1 PTCL 2 LGL-L 19 solid tumor | Median age 65 F:M, 27.6%:72.4% ECOG range, 0-1 ≥3 prior therapies: 86.2% | DLTs: 2 (stomatitis, arthralgia) No treatment-related serious AEs recorded Any AE Gr ≥3: 10% Arthralgia: 3.4% Stomatitis: 3.4% Decreased weight: 3.4% Most common AEs were grade 1/2 constipation, fatigue, nausea, and anemia | Best reported responses HL:PR CTCL cohort, n = 5: PR: 2 SD: 1 Solid tumor cohort SD: 4 | 94 | |
| NCT05233033 | KT-413 | IRAK4 | Cereblon | DLBCL (MYD88 mutated) | 1 | NA | 95 | ||||
| NCT04886622 | DT2216 | BCLXL | VHL | Various malignancies | 1 | NA | 96 | ||||
| NCT05487170 | RNK05047 | BRD4 | HSP90 chaperone complex | DLBCL | 1/2 | NA | 97 |
| Trial/clinical trial number . | PROTAC . | Target protein . | E3 ligase . | Disease context . | Clinical trial phase . | Patients, n . | Cohort description . | Additional cohort data . | Safety data . | Efficacy data . | References . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| NX-2127-001 NCT04830137 | NX-2127 | BTK/Ikaros/Aiolos | Cereblon | B-cell malignancies | 1 | Total: 54 33 CLL/SLL DLBCL, 6 MCL, 7 MZL, 3 WM, 3 FL, 2 | Median age: 72.5 y F:M, 31.5%:68.5% Median prior therapies: 4 CLL cohort: Median age: 74 y F:M, 33.3%:66.7% Median prior therapies: 5 NHL cohort: Median age: 70 y F:M, 28.6%:71.4% Median prior therapies: 4 | CLL cohort Previous BTKi: 100% Previous pirtobrutinib: 27.3% Previous BTKi & BCL2i: 78.8% BCL2 mutation: 12.1% BTK mutation: 36.4% | DLTs: 2 AE Gr ≥3: Neutropenia: 38.3% Hypertension: 14.9% Anemia: 12.8% Thrombocytopenia: 6.4% COVID-19: 6.4% Atrial fibrillation: 6.4% Pneumonia: 6.4% Leucocytosis: 6.4% Sepsis: 4.3% Increased lymphocyte count: 4.3% Pruritis: 2.1% Dyspnea: 2.1% | CLL evaluable cohort (n = 27) ORR: 40.7% PR: 40.7% SD: 44.4% PD: 14.8% NHL evaluable cohort (n = 17): CR: 11.8% PR: 11.8% SD: 29.4% PD: 47.1% | 88 |
| NX-5948-301 NCT05131022 | NX-5948 | BTK | Cereblon | B-cell malignancies | 1 | Total 26: 7 CLL 7 DLBCL 5 MCL 3 MZL 1 FL 1 PCNSL 2 WM | Median age: 65 y F:M, 28.6%:71.4% Median prior therapies: 4 | CLL cohort: Median age: 64 y F:M 28.6%:71.4% Median prior therapies: 3 TP53 aberrancy: 33.3% BTK mutation (T474): 16.7% PLCG1/2 mutation: 33.3% BCL2 mutation: 33.3% NHL/WM cohort: Median age: 63 y F:M 31.6%:68.4% Median prior therapies: 5 TP53 aberrancy: 20% | No DLTs recorded No treatment-related AE led to discontinuation AE Gr >3: Neutropenia: 19.2% Thrombocytopenia: 7.7% COVID-19: 7.7% Pneumonia: 7.7% Anemia: 3.8% | CLL evaluable cohort (n = 7) 3 PR (42.8%) 2 SD (28.5%) 2 PD (28.5%) NHL evaluable cohort: (n = 19) 2 PMR 1 PR 2 SD 13 PD | 89 89 |
| BGB-16673-101 NCT05006716 NCT05294731 | BGB-16673 | BTK | Undisclosed | B-cell malignancies | 1 | Total: 50 24 CLL/SLL 7 MCL 3 MZL 6 WM 2 DLBCL 6 FL 2 RT | Median age: 70.5 y F:M, 34%:66% Median prior therapies: 4 | CLL cohort unmutated IGHV: 84.2%, TP53 aberrancy: 45.8% Complex CG: 40% Whole cohort: Previous BTKi: 80% Previous BCL2i: 56% BTK mutation present: 29.2% PLCG2 mutation present: 8.3% BCL2 mutation present: 44.4% | No DLTs recorded Any AE Gr ≥3: 38% Treatment-related AE Gr ≥3: 22% Deaths: 4% AE Gr ≥3: Contusion: 30% Diarrhea: 24% Fatigue: 20% Increased amylase: 16% Neutropenia: 16% Increased lipase: 14% Pyrexia: 14% Cough: 12% Headache: 10% Pneumonia: 6% COVID-19 pneumonia: 4% AEs of interest Any bleeding: 42% Any infection: 50% Atrial fibrillation: 0% | Total evaluable cohort (n = 28): ORR: 54% CR: 4% PR/PR-L: 50% MR: 4% SD: 18% PD: 18% Ceased: 7% CLL evaluable cohort: (n = 10) PR/PR-L: 70% SD: 20% Ceased: 10% MCL/MZL/WM evaluable cohort (n = 16) CR: 6.3% PR: 43.8% MR: 6.3% SD: 18.8% PD 18.8% Ceased: 6.3% DLBCL/RT (n = 2) PD: 100% | 90 |
| NCT04861779 | HSK29116 | BTK | Undisclosed | B-cell malignancies | 1 | NA | 91 | ||||
| NCT05780034 | AC0676 | BTK | Undisclosed | B-cell malignancies | 1 | NA | 92 | ||||
| NCT05753501 | ABBV-101 | BTK | Undisclosed | B-cell malignancies | 1 | NA | 93 | ||||
| KT333-TL-101 NCT05225584 | KT-333 | STAT3 | Undisclosed | NHL, CTCL, LGL-L, PTCL | 1 | Total: 29 1 B-cell NHL 1 HL 5 CTCL 1 PTCL 2 LGL-L 19 solid tumor | Median age 65 F:M, 27.6%:72.4% ECOG range, 0-1 ≥3 prior therapies: 86.2% | DLTs: 2 (stomatitis, arthralgia) No treatment-related serious AEs recorded Any AE Gr ≥3: 10% Arthralgia: 3.4% Stomatitis: 3.4% Decreased weight: 3.4% Most common AEs were grade 1/2 constipation, fatigue, nausea, and anemia | Best reported responses HL:PR CTCL cohort, n = 5: PR: 2 SD: 1 Solid tumor cohort SD: 4 | 94 | |
| NCT05233033 | KT-413 | IRAK4 | Cereblon | DLBCL (MYD88 mutated) | 1 | NA | 95 | ||||
| NCT04886622 | DT2216 | BCLXL | VHL | Various malignancies | 1 | NA | 96 | ||||
| NCT05487170 | RNK05047 | BRD4 | HSP90 chaperone complex | DLBCL | 1/2 | NA | 97 |
AE, adverse event; BCLxL, B-cell lymphoma extralarge; BCL2, B-cell lymphoma protein 2; BRD, bromodomain; CG, cytogenetics; CR, complete response; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; DLT, dose-limiting toxicity; ECOG, Eastern Cooperative Oncology Group; F, female; FL, follicular lymphoma; Gr, grade; HL, Hodgkin lymphoma; IGHV, immunoglobulin heavy variable; IRAK, interleukin 1 receptor associated kinase; LGL-L, large granular lymphocytic leukemia; M, male; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; PR, partial response; PR-L, partial response with lymphocytosis; PD, progressive disease; PLCG1/2, phospholipase C gamma-1/2; PTCL, peripheral T-cell lymphoma; RT, Richter transformation; SD, stable disease; SLL, small lymphocytic lymphoma; ST, solid tumor; WM, Waldenstrom macroglobulinemia.