Clinical studies of replication stress response inhibitors in hematologic malignancies
| Inhibitor . | Phase . | Study . | Target . | Treatment . | Malignancy . | Number of patients . | ClinicalTrials.gov identifier . | Findings . |
|---|---|---|---|---|---|---|---|---|
| SRA737 | 1/2 | Sponsored by Sierra Oncology | CHK1 | Monotherapy | Advanced solid tumors or NHL | 107 | NCT02797964 | Completed in 2019, not reported |
| PEP07 | 1 | Sponsored by Pharmaengine | CHK1 | Monotherapy | Refractory AML and MCL | 32 | NCT05659732 | Ongoing |
| Prexasertib | 1 | Sponsored by M.D. Anderson Cancer Center | CHK1 | Combined with cytarabine and fludarabine | Refractory CML, AML, and MDS | 15 | NCT02649764 | Completed in 2022, not reported |
| Prexasertib | 1 | Sponsored by Dana-Farber Cancer Institute | CHK1 | Combined with mitoxantrone, etoposide, and cytarabine | Refractory AML and MDS | 2 | NCT03735446 | Terminated in 2019, not reported |
| Ceralasertib | 1/2 | Jurczak et al, 2023140 | ATR | Monotherapy; combined with acalabrutinib | Relapsed/refractory CLL | 11 | NCT03328273 | Ceralasertib alone showed limited clinical benefit. Acalabrutinib + ceralasertib was tolerable with limited preliminary clinical activity observed in 2 patients with BTK inhibitor-naïve, del(11q) CLL |
| Ceralasertib | 1 | Sponsored by AstraZeneca | ATR | Monotherapy | Refractory CLL, PLL, and B-cell NHL | 2 | NCT01955668 | Terminated in 2013, not reported |
| Ceralasertib | 1 | Sponsored by AstraZeneca | ATR | Monotherapy | Progressive MDS, CMML | 52 | NCT03770429 | Ongoing |
| Camonsertib | 1/2 | Hu et al, 2023141 | ATR | Combined with olaparib | Relapsed/refractory CLL | 45 | NCT05405309 | Ongoing |
| AZD1775 | 2 | Sponsored by Mayo Clinic | WEE1 | Monotherapy; combination with cytarabine | Refractory AML amd MDS | 3 | NCT02666950 | Terminated in 2019, not reported |
| MK-8776 | 2 | Webster et al, 2017142 | WEE1 | Combination with cytarabine | Refractory AML | 32 | NCT01870596 | Well tolerated. Combination therapy did not improve complete response rates or 1-year overall survival when compared with cytarabine alone, despite transiently increasing DNA damage in vivo |
| MK-8776 | 1 | Karp et al, 2012143 | WEE1 | Combination with cytarabine | Refractory AML, ALL, and CML | 24 | NCT00907517 | Cardiac and neurotoxic effects occurred at the WEE1 inhibitor dose of 80 mg/m2; 8 of 24 patients, including 2 with complex karyotype, treated with ≥80 mg/m2 WEE1 inhibitor doses attained complete remission. WEE1 inhibitor at 40 mg/m2 induced H2AX phosphorylation, a marker of DNA damage, in leukemic cells. |
| Adavosertib | 1 | Shafer et al, 2023144 | WEE1 | Combination with belinostat | Relapsed and refractory AML and MDS | 20 | NCT02381548 | Grade 4 CRS occurred at 225 mg per day adavosertib and 1000 mg per m2 belinostat, and was dose limiting. No clinical benefit was observed. |
| Inhibitor . | Phase . | Study . | Target . | Treatment . | Malignancy . | Number of patients . | ClinicalTrials.gov identifier . | Findings . |
|---|---|---|---|---|---|---|---|---|
| SRA737 | 1/2 | Sponsored by Sierra Oncology | CHK1 | Monotherapy | Advanced solid tumors or NHL | 107 | NCT02797964 | Completed in 2019, not reported |
| PEP07 | 1 | Sponsored by Pharmaengine | CHK1 | Monotherapy | Refractory AML and MCL | 32 | NCT05659732 | Ongoing |
| Prexasertib | 1 | Sponsored by M.D. Anderson Cancer Center | CHK1 | Combined with cytarabine and fludarabine | Refractory CML, AML, and MDS | 15 | NCT02649764 | Completed in 2022, not reported |
| Prexasertib | 1 | Sponsored by Dana-Farber Cancer Institute | CHK1 | Combined with mitoxantrone, etoposide, and cytarabine | Refractory AML and MDS | 2 | NCT03735446 | Terminated in 2019, not reported |
| Ceralasertib | 1/2 | Jurczak et al, 2023140 | ATR | Monotherapy; combined with acalabrutinib | Relapsed/refractory CLL | 11 | NCT03328273 | Ceralasertib alone showed limited clinical benefit. Acalabrutinib + ceralasertib was tolerable with limited preliminary clinical activity observed in 2 patients with BTK inhibitor-naïve, del(11q) CLL |
| Ceralasertib | 1 | Sponsored by AstraZeneca | ATR | Monotherapy | Refractory CLL, PLL, and B-cell NHL | 2 | NCT01955668 | Terminated in 2013, not reported |
| Ceralasertib | 1 | Sponsored by AstraZeneca | ATR | Monotherapy | Progressive MDS, CMML | 52 | NCT03770429 | Ongoing |
| Camonsertib | 1/2 | Hu et al, 2023141 | ATR | Combined with olaparib | Relapsed/refractory CLL | 45 | NCT05405309 | Ongoing |
| AZD1775 | 2 | Sponsored by Mayo Clinic | WEE1 | Monotherapy; combination with cytarabine | Refractory AML amd MDS | 3 | NCT02666950 | Terminated in 2019, not reported |
| MK-8776 | 2 | Webster et al, 2017142 | WEE1 | Combination with cytarabine | Refractory AML | 32 | NCT01870596 | Well tolerated. Combination therapy did not improve complete response rates or 1-year overall survival when compared with cytarabine alone, despite transiently increasing DNA damage in vivo |
| MK-8776 | 1 | Karp et al, 2012143 | WEE1 | Combination with cytarabine | Refractory AML, ALL, and CML | 24 | NCT00907517 | Cardiac and neurotoxic effects occurred at the WEE1 inhibitor dose of 80 mg/m2; 8 of 24 patients, including 2 with complex karyotype, treated with ≥80 mg/m2 WEE1 inhibitor doses attained complete remission. WEE1 inhibitor at 40 mg/m2 induced H2AX phosphorylation, a marker of DNA damage, in leukemic cells. |
| Adavosertib | 1 | Shafer et al, 2023144 | WEE1 | Combination with belinostat | Relapsed and refractory AML and MDS | 20 | NCT02381548 | Grade 4 CRS occurred at 225 mg per day adavosertib and 1000 mg per m2 belinostat, and was dose limiting. No clinical benefit was observed. |
BTK, Bruton tyrosine kinase; CMML, chronic myelomonocytic leukemia; CRS, cytokine release syndrome; MCL, mantle cell lymphoma; NHL, non-Hodgkin lymphoma.