Study of MLN8237 in Participants With Advanced Solid Tumors

NCT00962091 | Completed Phase 1 Results

• 2 other identifiers: C14010U1111-1187-6657
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

The purposes of this study were to estimate the relative (Rel) bioavailability (BA) of an oral solution (OS) formulation of alisertib in reference to a powder-in-capsule (PIC) formulation, to characterize the effect of food on the single-dose pharmacokinetics (PK) of alisertib OS and enteric-coated tablets (ECT), to characterize the multiple-dose safety, tolerability, and steady-state PK of alisertib administered as an OS, and to characterize the multiple-dose safety and tolerability of alisertib administered as an ECT.

Conditions

Advanced Solid Tumors

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (13)

• Part A: Dose-normalized Cmax (Maximum Observed Concentration) for Estimation of Relative Bioavailability for Alisertib Oral Solution (OS) Versus Powder in Capsule Formulations (PIC)

  Dose normalized Cmax was obtained using Cmax divided by alisertib dose in milligrams to provide values adjusted to a 1 mg alisertib dose.

  Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual adverse event (AE) that was judged by the investigator to be treatment related.

• Part A: Dose-normalized AUClast (Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration) for Estimation of Relative Bioavailability for Alisertib Oral Solution (OS) Versus Powder in Capsule Formulations (PIC)

  Dose normalized AUClast was obtained using Cmax divided by alisertib dose in milligrams to provide values adjusted to a 1 mg alisertib dose.

  Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

• Part B: Cmax: Maximum Observed Concentration for Alisertib Administered as an Oral Solution With Food Versus Without Food

  Not performed.

  Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

• Part B: AUClast: Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration for Alisertib Administered as an Oral Solution With Food Versus Without Food

  Not performed.

  Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

• Part B: Cmax: Maximum Plasma Concentration for Alisertib Oral Solution Following Multiple-Dose Administration

  Not performed.

  Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

• Part B: Tmax: Time of First Occurrence of Cmax Over the Dosing Interval for Alisertib Oral Solution Following Multiple-Dose Administration

  Not performed.

  Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

• Part B: AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval for Alisertib Oral Solution Following Multiple-Dose Administration

  Not performed.

  Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

• Part C: Cmax: Maximum Observed Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food

  Participants were randomized to receive 50-mg alisertib as an ECT (single, 50-mg strength tablets) under fasted or fed (following a standardized high-fat meal) conditions.

  Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

• Part C: AUClast: Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food

  Cycles 1 and 2 on Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

• Part C: AUC∞: Area Under the Concentration-Time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food

  Cycles 1 and 2 on Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  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.

  Up to 30 days after the last dose of study drug (up to 27.4 months)

• Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5%

  Laboratory AEs reported at an incidence of at least 5% overall in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, metabolism and nutrition disorders, investigations, and hepatobiliary disorders. Abnormal laboratory value were assessed as an AE if the value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 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.

  Up to 30 days after the last dose of study drug (up to 27.4 months)

• Number of Participants With Abnormal Vital Signs Reported as Adverse Events

  Vital signs (blood pressure, heart rate, and oral temperature) measurements were obtained throughout the study.

  Up to 30 days after the last dose of study drug (up to 24 months approximately)

Secondary Outcomes (1)

• Best Overall Response (CR+PR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

  At the completion of Cycle 2 and every 2 cycles (every 6 weeks) until Cycle 6 (18 weeks). After Cycle 6 (18 weeks), CT/MRI scans (with contrast) were to be performed every 3 cycles (9 weeks) until PD was documented.

Study Arms (7)

Dose Escalation

EXPERIMENTAL

A single dose of alisertib 15 mg, oral solution (OS) was administered on Day 1, followed by alisertib 40 mg, powder-in-capsule (PIC), orally, twice a day (BID) on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, was administered on Cycle 2 Day 1 followed by alisertib 40 mg on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Subsequent cycles, alisertib 40 or 50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.

Drug: Alisertib

Part A: Relative Bioavailability OS/PIC (Sequence A)

EXPERIMENTAL

A single dose of alisertib 25 mg, OS, administered on Day 1, followed by alisertib 40 mg PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, administered on Cycle 2 Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles, alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.

Drug: Alisertib

Part A: Relative Bioavailability PIC/OS (Sequence B)

EXPERIMENTAL

A single dose of alisertib 50 mg, PIC, orally administered on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 25 mg, OS, once on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.

Drug: Alisertib

Part B: OS Food Effect Fed/Fasted (Sequence A)

EXPERIMENTAL

Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose): A single dose of alisertib 35 mg oral solution (OS), in fed state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 35 mg administered, OS, in fasted state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg, PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted, based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.

Drug: Alisertib

Part B: OS Food Effect Fasted/Fed (Sequence B)

EXPERIMENTAL

A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.

Drug: Alisertib

Part C: ECT Food Effect Fed/Fasted (Sequence A)

EXPERIMENTAL

Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.

Drug: Alisertib

Part C: ECT Food Effect Fasted/Fed (Sequence B)

EXPERIMENTAL

Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.

Drug: Alisertib

Interventions

Alisertib DRUG

Alisertib OS Alisertib PIC Alisertib PIC

Also known as: MLN8237

Dose Escalation; Part A: Relative Bioavailability OS/PIC (Sequence A); Part A: Relative Bioavailability PIC/OS (Sequence B); Part B: OS Food Effect Fasted/Fed (Sequence B); Part B: OS Food Effect Fed/Fasted (Sequence A); Part C: ECT Food Effect Fasted/Fed (Sequence B); Part C: ECT Food Effect Fed/Fasted (Sequence A)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years or older
• Histologically or cytologically confirmed metastatic and/or advanced solid tumor
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse
• Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
• Voluntary written consent
• Suitable venous access for study-required blood sampling
• Measurable disease
• Recovered from effects of prior antineoplastic therapy
• Meet required entry laboratory and organ function levels

You may not qualify if:

• Female participants who are pregnant or lactating
• Serious medical or psychiatric illness that could interfere with protocol completion
• Major surgery within 14 days of first dose of alisertib
• Antineoplastic therapy, radiation therapy or any experimental therapy 21 days prior to first dose of alisertib
• Nitrosoureas or mitomycin-C within 6 weeks before the first dose of alisertib.
• Autologous stem cell transplant within 3 months before the first dose of alisertib, or prior allogeneic stem cell transplant at any time.
• Active infection requiring systemic therapy, or other serious infection
• Inability to swallow oral medication
• Gastrointestinal (GI) disease or GI procedure that could interfere with oral absorption or tolerance of alisertib
• Symptomatic brain metastasis
• Uncontrolled cardiovascular condition
• Diagnosis or treatment of another malignancy within 2 years preceding first dose of study drug except nonmelanoma skin cancer or in situ malignancy completely resected
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
• Lactose-intolerant (Parts A and B only)
• Prior history of metabolic acidosis (Parts A and B only)

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (1)

Premiere Oncology, A Medical Corporation

Santa Monica, California, 90404, United States

Location

Related Publications (2)

• Falchook GS, Zhou X, Venkatakrishnan K, Kurzrock R, Mahalingam D, Goldman JW, Jung J, Ullmann CD, Milch C, Rosen LS, Sarantopoulos J. Effect of Food on the Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib (MLN8237) in Patients with Advanced Solid Tumors. Drugs R D. 2016 Mar;16(1):45-52. doi: 10.1007/s40268-015-0114-8.

  PMID: 26689566 DERIVED

• Falchook GS, Venkatakrishnan K, Sarantopoulos J, Kurzrock R, Mita AC, Fu S, Mita MM, Zhou X, Jung JA, Ullmann CD, Milch C, Rosen LS. Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors. Int J Clin Pharmacol Ther. 2015 Jul;53(7):563-72. doi: 10.5414/CP202359.

  PMID: 26073352 DERIVED

MeSH Terms

Interventions

MLN 8237

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director Clinical Science

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2009
• First Posted: August 19, 2009
• Study Start: September 25, 2009
• Primary Completion: December 28, 2011
• Study Completion: July 1, 2014
• Last Updated: March 12, 2019
• Results First Posted: March 12, 2019

Record last verified: 2019-03

Locations

US (1)