Phase 1
Completed N=59
A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Participants With Advanced Malignancies
Advanced Malignancies
Source: ClinicalTrials.gov NCT00651664 ↗
Enrolled (actual)
59
Serious AEs
44.1%
Results posted
Mar 2019
Primary outcomePrimary: Number of Participants With Dose-Limiting Toxicity (DLT) — 0; 0; 0; 0 participants
Summary
This is a multicenter, dose escalation, phase 1 study of MLN8237 in adult participants with advanced malignancies (excluding those with primary bone marrow involvement, such as leukemias and multiple myeloma).
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Dose-Limiting Toxicity (DLT) |
0; 0; 0; 0; 2; 2 | — |
| PRIMARY Maximum Tolerated Dose (MTD) of Alisertib |
50 | — |
| SECONDARY Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing |
123.15; 1774.12; 2014.81; 1035.3; 1536.1; 1266.6 | — |
| SECONDARY Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing |
1.920; 2.730; 4.000; 2.040; 2.000; 2.000 | — |
| SECONDARY AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing |
975.0; 18204.2; 27262.7; 6314.1; 9771.5; 6895.3 | — |
| SECONDARY Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing |
18.25; 19.80; 15.913; 19.475; 18.500; 13.637 | — |
| SECONDARY Accumulation Ratio (Rac) for Alisertib 7 Day Dosing |
0.874; 0.892; 1.954; 2.295; 2.583; 7.765 | — |
| SECONDARY Peak/Trough Ratio for Aliserib 7 Day Dosing |
5.950; 4.650; 4.507; 3.083; 3.050; 1.867 | — |
| SECONDARY CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing |
14.055; 9.604; 5.967; 5.414; 4.182; 2.795 | — |
| SECONDARY Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing |
1145.4; 1418.1; 1671.1 | — |
| SECONDARY Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing |
2.030; 2.000; 2.000 | — |
| SECONDARY AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing |
15363.0; 17918.8; 16449.8 | — |
| SECONDARY Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing |
26.62 | — |
| SECONDARY Accumulation Ratio (Rac) for Alisertib 14 Day Dosing |
1.671; 1.813 | — |
| SECONDARY Peak/Trough Ratio for Aliserib 14 Day Dosing |
4.415; 7.412 | — |
| SECONDARY CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing |
5.381; 5.856 | — |
| SECONDARY Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing |
1112.3; 2220.3; 1524.1; 2595.0; 1651.7; 2093.7 | — |
| SECONDARY Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing |
4.000; 2.000; 2.070; 2.130; 2.100; 2.125 | — |
| SECONDARY AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing |
11701.0; 18953.4; 20262.8; 30918.3; 18264.9; 24515.6 | — |
| SECONDARY Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing |
20.13; 26.13 | — |
| SECONDARY Accumulation Ratio (Rac) for Alisertib 21 Day Dosing |
2.482; 2.103; 1.678; 1.933 | — |
| SECONDARY Peak/Trough Ratio for Aliserib 21 Day Dosing |
4.070; 3.628; 4.792; 4.658 | — |
| SECONDARY CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing |
4.753; 4.364; 5.276; 5.593 | — |
| SECONDARY Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing |
0.187; 0.107; 0.197; 0.310; 0.378; 0.175 | — |
| SECONDARY Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing |
1.180; 0.950; 1.146; 0.368 | — |
| SECONDARY Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing |
1.534; 1.900; 0.341; 1.168; 0.250; 0.565 | — |
| SECONDARY Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing |
0.080; 0.000; 0.097; 0.040; 0.000; 0.055 | — |
| SECONDARY Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing |
0.000; 0.390; 0.484; 0.260 | — |
| SECONDARY Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing |
0.606; 0.379; 0.146; 0.404; 0.134; 0.230 | — |
| SECONDARY Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing |
0.125; 0.610; 6.460; 1.464; 1.080; 0.090 | — |
| SECONDARY Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing |
0.008 | — |
| SECONDARY Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing |
0.027; 0.050; 0.014; 0.054 | — |
Eligibility Criteria
Inclusion Criteria
- Have a histologically or cytologically confirmed metastatic and/or advanced malignancy (including lymphomas but excluding malignancies with extensive bone marrow involvement such as leukemias and multiple myeloma) for which standard treatment does not offer curative or life-prolonging potential.
- Aged 18 years or more.
- Eastern Cooperative Oncology Group performance status 0 or 1.
- Have an expected survival longer than 3 months from enrollment in the study.
- Radiographically or clinically evaluable tumor.
- Suitable venous access for the conduct of blood sampling.
- Recovered from the reversible effects of prior antineoplastic therapy (with the exception of alopecia and grade 1 neuropathy) with at least 4 weeks elapsed since the last exposure to cytotoxic chemotherapy or to radiotherapy and at least 6 weeks elapsed since exposure to nitrosoureas or mitomycin C. Participants treated with fully human monoclonal antibodies must not have received treatment with such antibodies for at least 6 weeks, and those treated with chimeric monoclonal antibodies must not have received treatment with such antibodies for at least 4 weeks. Participants treated with noncytotoxic small molecule drugs (eg, tyrosine kinase inhibitors, such as Tarceva® [erlotinib], and hormonal agents, such as Femara® [letrozole]) must not have received treatment with these drugs for at least 2 weeks before the first dose of alisertib was given.
- Male participants must use an appropriate method of barrier contraception and inform any sexual partners that they must also use a reliable method of contraception from the time of informed consent until 3 months after the last dose of study treatment.
- Female participants must be postmenopausal at least 1 year, OR surgically sterile, OR if of childbearing potential, agree to 2 effective methods of nonhormonal contraception, or agree to completely abstain from heterosexual intercourse.
- Able to give written consent.
Exclusion Criteria
- Pregnant or lactating.
- Major surgery or serious infection within the 28 days preceding the first dose of study treatment.
- Life-threatening or uncontrolled medical illness unrelated to cancer.
- Ongoing nausea or vomiting of any severity.
- >Grade 1 diarrhea. Participants who require ongoing therapy with an antimotility agent to control diarrhea to a Grade 1 or lower level are not allowed to participate in this trial.
- Known gastrointestinal disease or gastrointestinal procedures that could interfere with the oral absorption or tolerance of MLN8237.
- History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness such as severe chronic obstructive pulmonary disease.
- Difficulty swallowing capsules.
- Inability to take nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of MLN8237.
- Received more than 4 previous cytotoxic chemotherapeutic regimens, including regimens used as adjuvant or neo-adjuvant therapies (in participants with metastatic breast cancer, a total of 5 previous cytotoxic chemotherapeutic regimens is permitted).
- Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution.
- Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow for the distribution of active bone marrow in adults).
- Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system metastasis but who have no radiographic or clinical evidence of residual tumor (eg, following complete surgical resection or stereotactic radiosurgery) are not excluded from participation in this study.
- Absolute neutrophil count(ANC) 1.6 mg/dL or a measured or estimated (Cockcroft-Gault formula) creatinine clearance 1.5 times the upper limi
Data sourced from ClinicalTrials.gov (NCT00651664). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.