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A Study of Alisertib (MLN8237) in Adult East Asian Participants With Advanced Solid Tumors or Lymphomas

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ClinicalTrials.gov Identifier: NCT01512758
Recruitment Status : Completed
First Posted : January 19, 2012
Results First Posted : March 15, 2019
Last Update Posted : March 15, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Lymphomas Drug: Alisertib Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 6, 2012
Actual Primary Completion Date : October 8, 2013
Actual Study Completion Date : October 8, 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Alisertib 30 mg
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.
Drug: Alisertib
Alisertib enteric-coated tablets
Other Name: MLN8237

Experimental: Alisertib 40 mg
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.
Drug: Alisertib
Alisertib enteric-coated tablets
Other Name: MLN8237




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) [ Time Frame: Treatment Cycle 1 ]
    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.

  2. Number of Participants With Adverse Events and Serious Adverse Events [ Time Frame: First dose to 30 days past last dose (Up to 12.1 Months) ]
    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.

  3. Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events [ Time Frame: First dose to 30 days past last dose (Up to 12.1 Months) ]
    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.

  4. Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events [ Time Frame: First dose to 30 days past last dose (Up to 12.1 Months) ]
    Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.

  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib [ Time Frame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose ]
    Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams.

  9. T1/2: Terminal Half-Life for Alisertib [ Time Frame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose ]
  10. Rac: Accumulation Ratio for Alisertib [ Time Frame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose ]
  11. 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 ]
  12. 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 Measures :
  1. Best Overall Response Rate Based on Investigator Assessment [ Time Frame: Baseline and every 2 cycles for up to 24 months or until progressive disease ]
    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.

  2. Duration of Response [ Time Frame: First documented response until disease progression; approximately 12 months ]
    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.

  3. 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01512758


Locations
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Singapore
National Cancer Centre
Tiong Bahru, Singapore, 169610
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01512758     History of Changes
Other Study ID Numbers: C14013
1015004128 ( Registry Identifier: TCTIN )
U1111-1187-6744 ( Registry Identifier: WHO )
First Posted: January 19, 2012    Key Record Dates
Results First Posted: March 15, 2019
Last Update Posted: March 15, 2019
Last Verified: November 2018

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
East Asian Patients
Advanced solid tumors
Lymphomas
MLN8237
Alisertib
Aurora A Kinase Inhibitor
Drug therapy

Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases