Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Pevonedistat · 8 trials · 12 indications
EFS was defined as the time from randomization to the date of an EFS event. An EFS event was defined as death or transformation to acute myelogenous leukemia (AML) (World Health Organization \[WHO\] classification as a participant having greater than 20 % blasts in the blood or marrow and an increase of blast count by 50%), whichever event occurred first, in participants with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemias (CMML). An EFS event was defined as death in participants with low-blast AML.
OS was defined as the time from the date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis were censored at the date the participant was last known to be alive. The Kaplan Meier estimates was used for the analysis.
Rate of study participants receiving Pevonedistat/VXLD therapy who experience dose limiting toxicities (DLTs), serious adverse events (SAEs) and and grade 3 or higher adverse events (AEs). Toxicities will be assessed in terms of nature, grade and attribution to protocol therapy using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03.
Determination of the maximum tolerated dose (MTD) of Pevonedistat/VXLD therapy for the purpose of obtaining a recommended phase 2 dose (RP2D) regimen
Change from time-matched baseline in QTcF was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. Data is reported at pre-dose and at multiple timepoints (1, 2, 3, 4, 6, 9, 11 and 24 hours) postdose up to Day 8 in Part A. Analysis of variance (ANOVA) was used for the analysis.
The Least square (LS) means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.
The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.
The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.
| Arm | Type | Description |
|---|---|---|
| Azacitidine 75 mg/m^2 | EXPERIMENTAL | Participants were administered azacitidine 75 milligram per square meter (mg/m\^2) intravenous (IV) or subcutaneous (SC) injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles. |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | EXPERIMENTAL | Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles. |
| Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2 | EXPERIMENTAL | Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). |
| Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2 | ACTIVE_COMPARATOR | Venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m\^2 intravenous (IV) or subcutaneous (SC) dosing on Days 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022. |
| Pevonedistat 20 mg/m^2 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2 | EXPERIMENTAL | Pevonedistat 20 mg/m\^2 as a 60-minute IV infusion on Days 1, 3, and 5 in each 28-day cycle plus venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m\^2 IV or SC dosing on Day 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022. |
| Dose Level 1: Pevonedistat 15 + VXLD | EXPERIMENTAL | * Pevonedistat: 15 mg/m2 intravenously (IV) * Vincristine: 1.5 mg/m2/dose IV push * Dexamethasone: 10 mg/m2/day divided twice daily * PEG-asparaginase: 2000 IU's/m2/day, capped at maximal dose of 3750 IU's. * Doxorubicin: 60 mg/m2/day IV * Intrathecal (IT) chemotherapy via injection per protocol: * All subjects: Cytarabine 70 mg ; * For central nervous system (CNS) negative subjects: Methotrexate 15 mg; * For CNS positive subjects (Triple IT Therapy): Cytarabine 30 mg, Methotrexate 15 mg, and Hydrocortisone 15 mg. |
| Dose Level -1: Pevonedistat 10 + VXLD | ACTIVE_COMPARATOR | * Pevonedistat: 10 mg/m2 IV * Vincristine: 1.5 mg/m2/dose IV push * Dexamethasone: 10 mg/m2/day divided twice daily * PEG-asparaginase: 2000 IU's/m2/day, capped at maximal dose of 3750 IU's. * Doxorubicin: 60 mg/m2/day IV * Intrathecal (IT) chemotherapy via injection per protocol: * All subjects: Cytarabine 70 mg ; * For CNS negative subjects: Methotrexate 15 mg; * For CNS positive subjects (Triple IT Therapy): Cytarabine 30 mg, Methotrexate 15 mg, and Hydrocortisone 15 mg. |
| Dose Level 2: Pevonedistat 20 + VXLD | ACTIVE_COMPARATOR | * Pevonedistat: 20 mg/m2 IV * Vincristine: 1.5 mg/m2/dose IV push * Dexamethasone: 10 mg/m2/day divided twice daily * PEG-asparaginase: 2000 IU's/m2/day, capped at maximal dose of 3750 IU's. * Doxorubicin: 60 mg/m2/day IV * Intrathecal (IT) chemotherapy via injection per protocol: * All subjects: Cytarabine 70 mg ; * For CNS negative subjects: Methotrexate 15 mg; * For CNS positive subjects (Triple IT Therapy): Cytarabine 30 mg, Methotrexate 15 mg, and Hydrocortisone 15 mg. |
| Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2 | EXPERIMENTAL | Pevonedistat 25 mg/m\^2, infusion, intravenously, once on Day 1 of Cycle 1, followed by pevonedistat 50 mg/m\^2, infusion, intravenously, once on Day 8 of Cycle 1. |
| Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2 | EXPERIMENTAL | Pevonedistat 50 mg/m\^2, infusion, intravenously, once on Day 1 of Cycle 1, followed by pevonedistat 25 mg/m\^2, infusion, intravenously, once on Day 8 of Cycle 1. |
| Part B: Pevonedistat | EXPERIMENTAL | Pevonedistat 25 mg/m\^2 in combination with docetaxel 75 mg/m\^2 or pevonedistat 20 mg/m\^2 in combination with carboplatin plus paclitaxel 175 mg/m\^2, infusion, intravenously, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 25 mg/m\^2 or 20 mg/m\^2 infusion, intravenously, once on Days 3 and 5 in each 21-day treatment cycle for up to 12 cycles or symptomatic deterioration or PD, treatment is discontinued for another reason, or until the study is stopped. The combination and dose of pevonedistat will be based on investigator discretion. |
| [14C]-Pevonedistat 25 mg/m^2 | EXPERIMENTAL | \[14C\]-pevonedistat (containing approximately 60-98 mCi \[approximately 2.22-3.626 MBq\] of radioactive tracer), infusion, intravenously, single dose on Day 1 of Week 1 in Part A. After completion of Part A, participants will have opportunity to continue into Part B. Participant will receive Pevonedistat 25 mg/m\^2, infusion, intravenously, single dose on Days 1, 3 and 5 of each 21 day cycle, for up to 12 cycles along with docetaxel 75 mg/m\^2, infusion, intravenously, over 1 hour on Day 1 of each 21 day cycle; or pevonedistat 20 mg/m\^2, infusion, intravenously, single dose on Days 1, 3 and 5 of each 21 day cycle, for up to 12 cycles, followed by paclitaxel 175 mg/m\^2, infusion, intravenously, over 3 hours along with carboplatin 20 mg/m\^2, infusion, intravenously, over 30 minutes on Day 1 of 21 each cycle up to 12 cycles. Based on investigator and sponsor discretion, participants deriving benefits will continue to receive current combination therapy or pevonedistat alone beyond 12 cycles. |
| Control Arm | EXPERIMENTAL | Pevonedistat 20 milligram per square meter (mg/m\^2), infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles. |
| Renal Arm | EXPERIMENTAL | Pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8-9 in combination with a starting dose of pevonedistat 10 mg/m\^2 to a maximum dose of pevonedistat 15 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles. |
| Mild Hepatic Arm | EXPERIMENTAL | Pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with a starting dose of pevonedistat 10 mg/m\^2 to a maximum dose of pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles. |
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | EXPERIMENTAL | Pevonedistat 50 milligram per square meter (mg/m\^2), intravenous infusion, once on Day 1 and 10 along with rifampin 600 milligram (mg), capsule, orally, once daily from Day 3 up to Day 11 in Part A. After completion of Part A, participants had opportunity to continue into optional Part B. |
| Name | Type | Description |
|---|---|---|
| Azacitidine | DRUG | Azacitidine intravenous or subcutaneous formulation. |
| Pevonedistat | DRUG | Pevonedistat intravenous infusion. |
| Venetoclax | DRUG | Venetoclax tablets. |
| Vincristine | DRUG | Administered each cycle on days 2, 9, 16 and 23. |
| Dexamethasone | DRUG | Taken orally each cycle on days 2 through 15. |
| PEG-asparaginase | DRUG | Administered via intramuscular injection (IM) each cycle on days 9 and 23. |
| Doxorubicin | DRUG | Administered via IV each cycle on day 2. |
| Cytarabine | DRUG | Administered to all subjects via IT injection on day 1; and on days 9, 16, and 23 to CNS positive subjects. |
| Methotrexate | DRUG | Administered via IT injection to CNS negative subjects on day 16; and to CNS positive subjects on days 9, 16 and 23. |
| Hydrocortisone | DRUG | Administered via IT injection to CNS positive subjects on days 9, 16, and 23. |
| Docetaxel | DRUG | Docetaxel intravenous infusion. |
| Carboplatin | DRUG | Carboplatin intravenous infusion. |
| Paclitaxel | DRUG | Paclitaxel intravenous infusion. |
| [14C]-Pevonedistat | DRUG | \[14C\]-Pevonedistat intravenous infusion. |
| Rifampin | DRUG | Rifampin capsules. |
Inclusion Criteria: 1. Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or CMML (i.e., with white blood cell \[WBC\] \<13,000/microliter \[mcL\]) or low-blast acute myelogenous leukemia (AML). 2. Has MDS or CMML and must also have one of the following Prognostic Risk Categ...
Top 20 of 34 competitors
Pevonedistat is an investigational small molecule being studied for the treatment of advanced solid tumors, acute myeloid leukemia (AML), myelodysplastic syndromes, refractory acute lymphoblastic leukemia, and other neoplasms. It is developed by Takeda Pharmaceutical Company Limited (TAK) and is currently in Phase 2 clinical development for these oncology indications.
Pevonedistat is a small molecule that targets NEDD8-activating enzyme (NAE), inhibiting the neddylation pathway. This disruption affects the degradation of proteins involved in cell cycle regulation and survival, which may lead to anti-tumor activity. The exact mechanism is under investigation in clinical trials.
Pevonedistat is developed by Takeda Pharmaceutical Company Limited, which trades under the ticker TAK. Takeda is conducting clinical trials to evaluate the drug's safety and efficacy in various oncology indications, including acute myeloid leukemia and myelodysplastic syndromes.
Pevonedistat is in Phase 2 clinical development. It is an investigational drug and has not been approved by regulatory authorities. Completed trials include Phase 1 and Phase 3 studies, but the most advanced ongoing development is at Phase 2 for acute myeloid leukemia and other conditions.
Pevonedistat has been studied in several clinical trials, including NCT02782468, a Phase 1 study in East Asian participants with AML and myelodysplastic syndromes; NCT03268954, a Phase 3 trial comparing pevonedistat plus azacitidine to azacitidine alone; NCT03330106, a Phase 1 QT interval study; and NCT04266795, a Phase 2 trial combining pevonedistat with venetoclax and azacitidine in AML.
Pevonedistat is also known by the code name TAK-924. This alternative name is used in some clinical and research contexts to refer to the same investigational drug developed by Takeda Pharmaceutical Company Limited.