Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Pevonedistat, TAK-924
MLN4924 · 12 trials · 15 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.
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.
DLT: Any of following events considered possibly related to study drug(s) by investigator: Grade (G) 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis; G3 diarrhea occurred despite maximal supportive therapy; G3 arthralgia/myalgia despite use of optimal analgesia; G3 nonhematologic toxicity with exceptions: 1) Brief fatigue, 2) hypophosphatemia; Persistent elevations of transaminases/bilirubin above G2 beyond 2 days between doses; Other study drug-related nonhematologic toxicities G2 or greater, required a dose reduction/discontinuation of pevonedistat. G3 or greater hematologic toxicities, including G3 or 4 febrile neutropenia, considered DLTs if: A delay in initiation of Cycle 2 due to lack of adequate recovery from treatment-related toxicity: 1) Of more than (\>) 4 weeks due to hematologic toxicity believed not related to leukemic infiltration. Bone marrow (BM) evaluation may have been required. 2) Of \>2 weeks due to nonhematologic toxicities.
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
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 + Azacitidine | ACTIVE_COMPARATOR | Participants received venetoclax 100 milligram (mg) tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Days 3 through 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 Days 1 through 21 or 28 as per Investigator's discretion. In addition, participants received azacitidine 75 milligrams per square meter (mg/m\^2) intravenous (IV) or subcutaneous (SC) dosing on Days 1 through 7 or Days 1 through 5, 8, and 9 in each cycle. |
| Pevonedistat + Venetoclax + Azacitidine | EXPERIMENTAL | Participants received pevonedistat 20 mg/m\^2 as a 60-minute IV infusion on Days 1, 3, and 5 in each 28-day cycle. In addition participants received venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Days 3 through 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. Participants also received azacitidine 75 mg/m\^2 IV or SC dosing on Days 1 through 7 or Days 1 through 5, 8, and 9 in each cycle. |
| 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. |
| MLN4924 + Fluconazole | EXPERIMENTAL | Part A: MLN4924, 8 milligram per square meter (mg/m\^2), intravenously, once on Days 1 and 8; and fluconazole, 400 milligram (mg), tablets, orally, once on Day 4, and 200 mg, once daily on Days 5-10. Part B: MLN4924, at a dose previously deemed tolerable, given on Days 1, 3, and 5 of each 21-day Cycle (Study C15010, Clinicaltrials.gov Identifier # NCT01862328) in combination with docetaxel or carboplatin + paclitaxel at standard dose regimen on Day 1 of each 21-day Cycle. |
| MLN4924 + Itraconazole | EXPERIMENTAL | Part A: MLN4924, 8-mg/m\^2, intravenously, once on Days 1 and 8; and itraconazole, 200 mg, oral solution, once daily on Days 4-10. Part A (safety lead-in step): MLN4924, 15mg/m\^2, intravenously, once on Days 1 and 8; and itraconazole, 200 mg, oral solution, once daily on Days 4-10. Part A: MLN4924, 20mg/m\^2, intravenously, once on Days 1 and 8; and itraconazole, 200 mg, oral solution, once daily on Days 4-10. Part B: MLN4924, at a dose previously deemed tolerable given, on Days 1, 3, and 5 of each 21-day Cycle (Study C15010, ClinicalTrails.gov Identifier # NCT01862328) in combination with docetaxel or carboplatin + paclitaxel at standard dose regimen on Day 1 of each 21-day Cycle. |
| [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. |
| Arm 1, Cohort 1: Pevonedistat 25 mg/m^2 | EXPERIMENTAL | Pevonedistat, 25 milligram per square meter (mg/m\^2), 60-minute infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in 21-day treatment cycles. |
| Arm 1, Cohort 2: Pevonedistat 44 mg/m^2 | EXPERIMENTAL | Pevonedistat, 44 mg/m\^2, 60-minute infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in 21-day treatment cycles. |
| Arm 2, Cohort 1: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 | EXPERIMENTAL | Pevonedistat 10 mg/m\^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m\^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles. |
| Arm 2, Cohort 2: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 | EXPERIMENTAL | Pevonedistat 20 mg/m\^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m\^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles. |
| 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. |
| MLN4924 and Docetaxel (Arm 1) | EXPERIMENTAL | - |
| MLN4924 + Paclitaxel + Carboplatin (Arm 2) | EXPERIMENTAL | - |
| MLN4924 + Gemcitabine (Arm 3) | EXPERIMENTAL | - |
| 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. |
| MLN4924 and Azacitidine | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| Azacitidine | DRUG | Azacitidine intravenous or subcutaneous formulation. |
| Pevonedistat | DRUG | Pevonedistat intravenous infusion. |
| Venetoclax | DRUG | Venetoclax tablets. |
| Docetaxel | DRUG | Docetaxel intravenous infusion. |
| Carboplatin | DRUG | Carboplatin intravenous infusion. |
| Paclitaxel | DRUG | Paclitaxel intravenous infusion. |
| MLN4924 | DRUG | MLN4924 intravenous solution. |
| Fluconazole | DRUG | Fluconazole tablets. |
| Itraconazole | DRUG | Itraconazole oral solution. |
| [14C]-Pevonedistat | DRUG | \[14C\]-Pevonedistat intravenous infusion. |
| Pevonedistat 25 mg/m^2 | DRUG | Pevonedistat 25 mg/m\^2 intravenous infusion. |
| Pevonedistat 44 mg/m^2 | DRUG | Pevonedistat 44 mg/m\^2 intravenous infusion. |
| Pevonedistat 10 mg/m^2 | DRUG | Pevonedistat 10 mg/m\^2 intravenous infusion. |
| Pevonedistat 20 mg/m^2 | DRUG | Pevonedistat 20 mg/m\^2 intravenous infusion. |
| Azacitidine 75 mg/m^2 | DRUG | Azacitidine 75 mg/m\^2 intravenous or subcutaneous formulation. |
| 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. |
| Gemcitabine | DRUG | Gemcitabine (IV) in participants in a 28-day cycle: -Gemcitabine on Days 1,8,15 of each cycle |
| 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...
MLN4924 is an investigational small molecule being studied in oncology for acute myelogenous leukemia, advanced solid tumors, and solid tumors. It has been evaluated in Phase 1 clinical trials, including a study in treatment-naive AML patients aged 60 years or older and studies in advanced solid tumors.
MLN4924 is being developed by Takeda Pharmaceutical Company Limited, which trades under the ticker TAK. Takeda is the sponsor of the clinical trials evaluating MLN4924 in acute myelogenous leukemia and solid tumors.
MLN4924 is in Phase 1 clinical development. It is investigational and has not been approved for any indication. The Phase 1 trials have been completed, including studies in acute myelogenous leukemia and advanced solid tumors.
MLN4924 has been evaluated in Phase 1 trials including NCT02122770, which studied CYP3A-mediated drug interactions in advanced solid tumors; NCT01862328, a dose-escalation study combining MLN4924 with docetaxel, gemcitabine, or carboplatin and paclitaxel in solid tumors; and NCT01814826, which tested MLN4924 plus azacitidine in treatment-naive AML patients aged 60 or older.
MLN4924 is not FDA approved. It is an investigational agent that has been studied in Phase 1 clinical trials for acute myelogenous leukemia and solid tumors. No regulatory approval has been granted for any indication.