Back to resultsA Study of Alisertib (MLN8237) in Adult East Asian Participants With Advanced Solid Tumors or Lymphomas
Primary Purpose
Advanced Solid Tumors, Lymphomas
Status
Completed
Phase
Phase 1
Locations
Singapore
Study Type
Interventional
Intervention
Alisertib
Sponsored by
About this trial
This is an interventional treatment trial for Advanced Solid Tumors focused on measuring East Asian Patients, Advanced solid tumors, Lymphomas, MLN8237, Alisertib, Aurora A Kinase Inhibitor, Drug therapy
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
Sites / Locations
- National Cancer Centre
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Alisertib 30 mg
Alisertib 40 mg
Arm Description
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 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.
Outcomes
Primary Outcome Measures
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
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.
Number of Participants With Adverse Events and Serious Adverse Events
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.
Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events
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.
Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events
Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
Cmax: Maximum Observed Concentration for Alisertib
Tmax: Time to First Occurrence of Cmax for Alisertib
AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib
Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib
Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams.
T1/2: Terminal Half-Life for Alisertib
Rac: Accumulation Ratio for Alisertib
PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib
CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib
Secondary Outcome Measures
Best Overall Response Rate Based on Investigator Assessment
Best overall response rate is defined as the percentage of participants with complete response (CR) and/or partial response (PR) as assessed by the Investigator using Lymphoma International Working Group (IWG) Criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT, PET or MRI. IWG criteria for CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. RECIST response criteria is defined as: 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.
Duration of Response
DOR is defined as the time from the date of first documentation of a CR response to the date of first documentation of PD according to IWG criteria or RECIST criteria 1.1. IWG PD is defined as PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. RECIST PD is defined as unequivocal progression of existing non-target lesions.
Concentrations of Relevant Tumor Markers
Full Information
NCT ID
NCT01512758
First Posted
January 13, 2012
Last Updated
November 29, 2018
Sponsor
Millennium Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT01512758
Brief Title
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
2. Study Status
Record Verification Date
November 2018
Overall Recruitment Status
Completed
Study Start Date
February 6, 2012 (Actual)
Primary Completion Date
October 8, 2013 (Actual)
Study Completion Date
October 8, 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Millennium Pharmaceuticals, Inc.
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Solid Tumors, Lymphomas
Keywords
East Asian Patients, Advanced solid tumors, Lymphomas, MLN8237, Alisertib, Aurora A Kinase Inhibitor, Drug therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
36 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Alisertib 30 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Alisertib 40 mg
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Alisertib
Other Intervention Name(s)
MLN8237
Intervention Description
Alisertib enteric-coated tablets
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
Description
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.
Time Frame
Treatment Cycle 1
Title
Number of Participants With Adverse Events and Serious Adverse Events
Description
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.
Time Frame
First dose to 30 days past last dose (Up to 12.1 Months)
Title
Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events
Description
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.
Time Frame
First dose to 30 days past last dose (Up to 12.1 Months)
Title
Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events
Description
Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
Time Frame
First dose to 30 days past last dose (Up to 12.1 Months)
Title
Cmax: Maximum Observed Concentration for Alisertib
Time Frame
Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose
Title
Tmax: Time to First Occurrence of Cmax for Alisertib
Time Frame
Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose
Title
AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib
Time Frame
Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose
Title
Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib
Description
Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams.
Time Frame
Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Title
T1/2: Terminal Half-Life for Alisertib
Time Frame
Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Title
Rac: Accumulation Ratio for Alisertib
Time Frame
Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Title
PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib
Time Frame
Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Title
CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib
Time Frame
Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Secondary Outcome Measure Information:
Title
Best Overall Response Rate Based on Investigator Assessment
Description
Best overall response rate is defined as the percentage of participants with complete response (CR) and/or partial response (PR) as assessed by the Investigator using Lymphoma International Working Group (IWG) Criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT, PET or MRI. IWG criteria for CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. RECIST response criteria is defined as: 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.
Time Frame
Baseline and every 2 cycles for up to 24 months or until progressive disease
Title
Duration of Response
Description
DOR is defined as the time from the date of first documentation of a CR response to the date of first documentation of PD according to IWG criteria or RECIST criteria 1.1. IWG PD is defined as PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. RECIST PD is defined as unequivocal progression of existing non-target lesions.
Time Frame
First documented response until disease progression; approximately 12 months
Title
Concentrations of Relevant Tumor Markers
Time Frame
Cycle 1, Day 1; at end of Cycle 2 and every 2 cycles thereafter; and at end treatment; approximately 12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director Clinical Science
Organizational Affiliation
Millennium Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
National Cancer Centre
City
Tiong Bahru
ZIP/Postal Code
169610
Country
Singapore
12. IPD Sharing Statement
Citations:
PubMed Identifier
26084989
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.
Results Reference
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A Study of Alisertib (MLN8237) in Adult East Asian Participants With Advanced Solid Tumors or Lymphomas
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