Clinical trial NCT01512758: A Study of Alisertib (MLN8237) in Adult East Asian Participants With Advanced Solid Tumors or Lymphomas
Official title: A Phase 1 Dose Escalation and Pharmacokinetic Study of Alisertib (MLN8237), an Aurora A Kinase Inhibitor, in Adult East Asian Patients With Advanced Solid Tumors or Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Lymphomas
Keywords: East Asian Patients
Advanced solid tumors
Lymphomas
MLN8237
Alisertib
Aurora A Kinase Inhibitor
Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2012-01-19
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to determine the safety profile, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and to characterize the pharmacokinetic (PK) profile of alisertib twice daily (BID) dosing for 7 days in East Asian participants with advanced solid tumors or lymphomas. The secondary objective was to describe any antitumor activity that may have been observed with alisertib treatment.

Detailed description: The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have advanced solid tumors or lymphomas for which standard curative or life-prolonging treatment did not exist or was no longer effective or tolerable. This study evaluated the safety and pharmacokinetic (PK) profile, and maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of alisertib, as well as any antitumor activity.

The study enrolled 36 patients. Participants were assigned to one of the two treatment groups and received:

* Alisertib 30 mg
* Alisertib 40 mg All participants took two enteric-coated tablets every 12 hours each day for 7 days followed by a 14-day rest period in a 21-day cycle for up to 16 cycles.

This multi-center trial is conducted in East Asia. The overall time to participate in this study was 24 months, unless it was determined that a participant would derive benefit from continued therapy beyond 24 months. Participants made multiple visits to the clinic, and were contacted up to a maximum of 30 days after last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

* Male or female East Asian participants 18 years or older
* Histologically or cytologically confirmed metastatic and/or advanced solid tumors or lymphomas for which no effective standard treatment is available
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Expected survival longer than 3 months from study enrollment
* Radiographically or clinically evaluable tumor
* Female participants who are post menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 30 days after the last dose of study drug or agree to abstain from heterosexual intercourse
* Male participants who agree to practice effective barrier contraception through 6 months after the last dose of alisertib or agree to abstain from heterosexual intercourse
* Voluntary written consent

Exclusion Criteria:

* Female participants who are lactating or pregnant
* Treatment with any investigational products, systemic antineoplastic treatment, or antineoplastic treatment with glucocorticoids within 21 days preceding the first dose of alisertib
* Treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other unconjugated antibody treatment within 42 days (21 days if clear evidence of progressive disease)
* Medical conditions requiring daily, chronic, or regular use of proton pump inhibitors or H2-receptor antagonists
* Treatment with radioimmunoconjugates such as ibritumomab tiuxetan or tositumomab within 56 days preceding first alisertib dose
* Major surgery within the 14 days preceding the first dose of alisertib
* Life-threatening or uncontrolled medical illness unrelated to cancer
* Known gastrointestinal (GI) disease or procedures that could interfere with the oral absorption or tolerance of alisertib
* Inability to swallow capsules
* Inadequate bone marrow or other organ function
* Diagnosed or treated for another malignancy within 2 years of first dose of alisertib, or previously diagnosed with another malignancy and have any radiographic or biochemical marker evidence of active disease. In the case of prior prostate cancer treated with radiotherapy, the prostate specific antigen (PSA) may be detectable, but must be \< 1 ng/mL. Participants with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy of any type are not excluded
* Other severe acute or chronic medical or psychiatric conditions, including uncontrolled diabetes, or laboratory abnormality
* Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
timeFrame: Treatment Cycle 1
measure: Number of Participants With Adverse Events and Serious Adverse Events
timeFrame: First dose to 30 days past last dose (Up to 12.1 Months)
measure: Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events
timeFrame: First dose to 30 days past last dose (Up to 12.1 Months)
measure: Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events
timeFrame: First dose to 30 days past last dose (Up to 12.1 Months)
measure: Cmax: Maximum Observed Concentration for Alisertib
timeFrame: Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose
measure: Tmax: Time to First Occurrence of Cmax for Alisertib
timeFrame: Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose
measure: AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib
timeFrame: Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose
measure: Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib
timeFrame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
measure: T1/2: Terminal Half-Life for Alisertib
timeFrame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
measure: Rac: Accumulation Ratio for Alisertib
timeFrame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
measure: PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib
timeFrame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
measure: CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib
timeFrame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Secondary outcomes:
measure: Best Overall Response Rate Based on Investigator Assessment
timeFrame: Baseline and every 2 cycles for up to 24 months or until progressive disease
measure: Duration of Response
timeFrame: First documented response until disease progression; approximately 12 months
measure: Concentrations of Relevant Tumor Markers
timeFrame: Cycle 1, Day 1; at end of Cycle 2 and every 2 cycles thereafter; and at end treatment; approximately 12 months
Other outcomes:
Locations:
city: Tiong Bahru
country: Singapore
facility: National Cancer Centre
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References:
citation: Venkatakrishnan K, Kim TM, Lin CC, Thye LS, Chng WJ, Ma B, Chen MH, Zhou X, Liu H, Kelly V, Kim WS. Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in East Asian cancer patients: pharmacokinetics and recommended phase 2 dose. Invest New Drugs. 2015 Aug;33(4):942-53. doi: 10.1007/s10637-015-0258-y. Epub 2015 Jun 19.