Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as [^14C]-alisertib, MLN8237, Aurora A kinase inhibitor MLN8237
Alisertib · 14 trials · 35 indications
ORR was defined as the percentage of participants who achieve Complete Response (CR) or Partial Response (PR) as assessed by the IRC using International Working Group (IWG) criteria. CR=Disappearance of all evidence of disease and PR=Regression of measurable disease and no new sites.
PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurred first.
Best overall response rate is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the Investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites (as specified in the Cheson 2007, IWG response criteria).
Best ORR is defined as the number of participants with complete remission(CR) or partial remission(PR) assessed by the Investigator using modified AML/MDS International Working Group(IWG) Criteria. AML:CR=neutrophils \>1x10\^9/L, platelets \>100x10\^9/L, bone marrow blasts(BMB) \<5%, transfusion independent, no extramedullary disease(EMD); CRi=BMB \<5%, transfusion independent, no EMD; PR=neutrophils \>1x10\^9/L, platelets \>100x10\^9/L, BMB \>50% decrease and 5% to 25%, blasts \<5% with Auer rods; PRi=BMB \>50% decrease and 5% to 25%. MDS:CR=bone marrow: ≤5% myeloblasts with normal maturation, peripheral blood: hemoglobin ≥11 g/dL, platelets ≥100x10\^9/L, neutrophils ≥1.0x10\^9/L, blasts 0%; PR=all CR criteria if abnormal before treatment except: BMB decreased by ≥50% over pretreatment but still \>5%; PRi=BMB decreased by ≥50% over pretreatment but still \>5%; Marrow CR=bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment, peripheral blood hematologic improvement responses noted.
Combined objective response rate is defined as the percentage of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 or response by Cancer antigen (CA) 125 criteria. According to RECIST: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions. CA 125 response criteria is defined as either: A 50% decrease from 2 initially elevated samples; the sample demonstrating the 50% decrease must have been confirmed by a fourth sample 28 days later (a total of 4 samples required) or A serial decrease of \> 75% over 3 samples; the third sample was to be obtained 28 days after the second (a total of 3 samples required).
PFS is defined as time in days from start of study treatment to first documentation of objective tumor progression based on Investigator's assessment or up to death due to any cause, whichever occurs first based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Progressive disease (PD) was defined as ≥20% increase in sum longest diameter (LD) in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
DLT was evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and was defined as any of the following events related to therapy with alisertib:1. Grade 4 neutropenia lasting ≥7 consecutive days, 2. Grade 4 neutropenia with fever and/or infection 3. Platelet count \<25,000/mm\^3 4. Grade 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis 5. Grade 3 or greater diarrhea despite maximal supportive therapy with loperamide 6. Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (\<1 week) Grade 3 fatigue 7. Treatment delay of \>21 days due to failure of adequate hematologic or non-hematologic recovery from previous cycle of treatment 8. Other alisertib related non-hematologic toxicities ≥Grade 2 that, in the opinion of the investigator required a dose reduction or discontinuation of therapy with alisertib.
MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants.
MTD was defined as highest dose at which \<2 participants experienced a dose-limiting toxicity (DLT). DLT was defined as any of the following events considered possibly related to therapy with alisertib by the investigator: 1. Grade 4 neutropenia (absolute neutrophil count \<500 cells/mm\^3) for \>7 days; 2. Grade 4 neutropenia with fever (oral or ear temperature ≥38.5°C); 3. Grade 4 thrombocytopenia (platelets \<25,000/mm\^3) for \>7 days; 4. Platelet count \<10,000 cells/mm\^3; 5. ≥Grade 3 thrombocytopenia with clinically significant bleeding; 6. Delay in initiation of subsequent cycle by \>7 days due to treatment-related toxicity; 7. ≥Grade 3 nonhematological toxicity except following: a. ≥Grade 3 nausea and/or emesis in the absence of optimal antiemetic therapy; b. ≥Grade 3 diarrhea in the absence of optimal supportive therapy; c. Grade 3 fatigue lasting \<1 week; d. Other Grade 3 nonhematological toxicity that can be safely and reliably controlled to ≤Grade 2 with appropriate treatment.
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Laboratory AEs in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, investigations, and metabolism and nutrition disorders. An abnormal laboratory value was assessed as an AE if that value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment¬-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams.
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
| Arm | Type | Description |
|---|---|---|
| Alisertib | EXPERIMENTAL | Alisertib 50 mg, enteric-coated tablet formulation, orally, twice daily for 7 consecutive days (Cycle Days 1-7) in a 21-day cycle (Up to 148 Weeks). |
| Pralatrexate, or Romidepsin, or Gemcitabine | ACTIVE_COMPARATOR | Pralatrexate 30 mg/m\^2, intravenous (IV) push over 3 to 5 minutes, once weekly, for 6 weeks in 7-week cycles with concurrent vitamin B12 and folic acid supplementation. Cycles were repeated every 7-weeks provided the participant continued to benefit from and tolerate the therapy (Up to 115 Weeks), or Gemcitabine 1,000 mg/m\^2 over 30 minutes, intravenously, on Days 1, 8, and 15 of a 28-day cycle until the absence of disease progression or unacceptable toxicity (Up to 32 Weeks), or Romidepsin 14 mg/m\^2, intravenously over a 4-hour period, on Days 1, 8, and 15 of a 28-cycle. Cycles were repeated every 28 days provided the patient continued to benefit from and tolerate the therapy (Up to 30 Weeks). |
| Alisertib 50 mg | EXPERIMENTAL | Alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 24 months or longer with Sponsor approval). |
| Alisertib (MLN8237) + Paclitaxel | EXPERIMENTAL | Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day until disease progression (Up to 17 Cycles). |
| Placebo + Paclitaxel | PLACEBO_COMPARATOR | Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles). |
| Alisertib 50 mg Fed + Fasted | EXPERIMENTAL | Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 50 mg, ECT, orally, twice daily (BID) on Days 4 through 10, followed by a 14-day rest period in Cycle 1 (24-day cycles), followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 50 mg, ECT, orally, BID on Days 4 through 10, followed by a 14-day rest period in Cycle 2, followed by alisertib 50 mg, ECT, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3 and onwards (21-day cycles) until disease progression, occurrence of an unacceptable alisertib-related toxicity. |
| Alisertib 50 mg Fasted + Fed | EXPERIMENTAL | Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 50 mg, ECT, orally, BID on Days 4 through 10, followed by a 14-day rest period in Cycle 1 (24-day cycles), followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 50 mg, ECT, orally, BID on Days 4 through 10, followed by a 14-day rest period in Cycle 2, followed by alisertib 50 mg, ECT, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3 and onwards (21-day cycles) until disease progression, occurrence of an unacceptable alisertib-related toxicity. |
| Alisertib: Normal Hepatic Function | EXPERIMENTAL | Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range \[ULN\] and alanine aminotransferase \[ALT\] level ≤ ULN. |
| Alisertib: Moderate Hepatic Impairment | EXPERIMENTAL | Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin \> 1.5-3 x ULN and any ALT level. |
| Alisertib: Severe Hepatic Impairment | EXPERIMENTAL | Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin \> 3 x ULN and any ALT level. |
| Part 1: PIC Dose Escalation | EXPERIMENTAL | Alisertib 25 or 35 mg, Powder-in-Capsule (PIC) formulation, orally, once daily (QD) for 21 days followed by a 7-day recovery period in 28-day cycles or alisertib 35, 45, 65 or 90 mg PIC, orally, (QD for 14 days followed by a 14-day recovery period in 28-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 14 cycles). All participants received an initial starting dosage of alisertib PIC 25 mg, orally, twice daily (BID) on Day 1 (loading dose), followed by their respective dosage assignment. |
| Part 1: ECT Dose Escalation | EXPERIMENTAL | Alisertib 40 mg, Enteric-coated Tablet (ECT) formulation, orally, QD for 14 days followed by a 14-day recovery period in 28-day cycles, or alisertib 30, 40 or 50 mg ECT, orally BID for 7 days followed by a 14-day recovery period in 21-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles). |
| Part 2: PTCL | EXPERIMENTAL | Participants with peripheral T-cell lymphoma (PTCL) received alisertib 50 mg ECT, orally, BID for 7 days followed by a 14-day recovery period in 21-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles). |
| Treatment (alisertib, gemcitabine) | EXPERIMENTAL | Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and alisertib PO BID on days 1-3, 8-10, and 15-17. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Esomeprazole 40 mg + Alisertib 50 mg | EXPERIMENTAL | Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Esomeprazole, 40 mg, delayed-release capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles). |
| Rifampin 600 mg + Alisertib 50 mg | EXPERIMENTAL | Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 in Cycle 2 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles). |
| Alisertib 30 mg | EXPERIMENTAL | Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2. |
| Alisertib 40 mg | EXPERIMENTAL | Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2. |
| Alisertib 5 mg QD 7D | EXPERIMENTAL | Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). |
| Alisertib 80 mg QD 7D | EXPERIMENTAL | Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). |
| Alisertib 150 mg QD 7D | EXPERIMENTAL | Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). |
| Alisertib 50 mg BID 7D | EXPERIMENTAL | Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). |
| Alisertib 60 mg BID 7D | EXPERIMENTAL | Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). |
| Alisertib 75 mg BID 7D | EXPERIMENTAL | Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). |
| Alisertib 100 mg BID 7D | EXPERIMENTAL | Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles). |
| Alisertib 50 mg QD 14D | EXPERIMENTAL | Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles). |
| Alisertib 50 mg QD 21D | EXPERIMENTAL | Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). |
| Alisertib 70 mg QD 21D | EXPERIMENTAL | Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles). |
| PIC Dose Escalation | EXPERIMENTAL | Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, Powder-in-Capsule (PIC) formulation, orally, once daily (QD) for 7 to 21 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 51 cycles). |
| ECT Dose Escalation | EXPERIMENTAL | Alisertib 10 or 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles). |
| Relative Bioavailability | EXPERIMENTAL | Alisertib 40 mg ECT or PIC formulation, orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 2, followed by alisertib 50 mg PIC formulation orally, twice daily (BID) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 9 cycles). |
| Name | Type | Description |
|---|---|---|
| Alisertib | DRUG | Alisertib enteric coated tablets |
| Pralatrexate | DRUG | Pralatrexate IV infusion |
| Gemcitabine | DRUG | Gemcitabine IV infusion |
| Romidepsin | DRUG | Romidepsin IV infusion |
| Placebo | DRUG | Placebo matching tablets |
| Paclitaxel | DRUG | Paclitaxel intravenous injection |
| Esomeprazole | DRUG | Esomeprazole capsules |
| Rifampin | DRUG | Rifampin capsules |
| [^14C]-alisertib | DRUG | \[\^14C\]-alisertib oral solution |
Inclusion Criteria: * Male or female participants age 18 or older * Participants with Peripheral T cell lymphoma (PTCL) (selected subtypes) according to World Health Organization (WHO) criteria and have relapsed or are refractory to at least 1 prior systemic, cytotoxic therapy for PTCL. Participant...
Alisertib is an investigational small molecule oncology drug developed by Takeda Pharmaceutical Company Limited. It has been studied in acinar cell adenocarcinoma of the pancreas, acute myelogenous leukemia, advanced malignancies, advanced solid tumors, B-cell follicular lymphoma, and diffuse large B-cell lymphoma. It is not approved and remains in clinical development.
Alisertib targets AURKA, also known as Aurora kinase A. It acts as an inhibitor of this target. By inhibiting AURKA, alisertib interferes with processes that cancer cells rely on during division. This mechanism underlies its investigation across solid tumors and hematologic malignancies.
Alisertib is developed by Takeda Pharmaceutical Company Limited, which trades under the ticker TAK. Takeda has sponsored the clinical trial program for the drug, including studies in advanced solid tumors, lymphoma, pancreatic cancer, and small cell lung cancer.
Alisertib is in Phase 1 development. It is investigational and has not been approved by the FDA. The clinical program includes Phase 1 and Phase 2 studies, all of which are completed, and no trials are currently active.
Four completed alisertib trials are registered. NCT02214147 studied pharmacokinetics in advanced solid tumors or relapsed/refractory lymphoma with varying hepatic function. NCT02038647 tested alisertib plus paclitaxel in small cell lung cancer. NCT01924260 combined alisertib with gemcitabine in solid tumors or pancreatic cancer, and NCT01898078 was a food effect study.
Yes, [^14C]-alisertib is another name for alisertib. The carbon-14 label refers to a radiolabeled form used in study work, while alisertib is the compound name. Both refer to the same AURKA inhibitor developed by Takeda.