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

NCT01512758 | Completed Phase 1 Results

• 3 other identifiers: C140131015004128U1111-1187-6744
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Advanced Solid Tumors; Lymphomas

Keywords

East Asian Patients; Advanced solid tumors; Lymphomas; MLN8237; Alisertib; Aurora A Kinase Inhibitor; Drug therapy

Outcome Measures

Primary Outcomes (12)

• 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.

  Treatment Cycle 1

• 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.

  First dose to 30 days past last dose (Up to 12.1 Months)

• 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.

  First dose to 30 days past last dose (Up to 12.1 Months)

• 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.

  First dose to 30 days past last dose (Up to 12.1 Months)

• Cmax: Maximum Observed Concentration for Alisertib

  Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose

• Tmax: Time to First Occurrence of Cmax for Alisertib

  Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose

• AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib

  Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose

• 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.

  Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

• T1/2: Terminal Half-Life for Alisertib

  Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

• Rac: Accumulation Ratio for Alisertib

  Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

• PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib

  Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

• CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib

  Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

Secondary Outcomes (3)

• Best Overall Response Rate Based on Investigator Assessment

  Baseline and every 2 cycles for up to 24 months or until progressive disease

• Duration of Response

  First documented response until disease progression; approximately 12 months

• Concentrations of Relevant Tumor Markers

  Cycle 1, Day 1; at end of Cycle 2 and every 2 cycles thereafter; and at end treatment; approximately 12 months

Study Arms (2)

Alisertib 30 mg

EXPERIMENTAL

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 40 mg

EXPERIMENTAL

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

Interventions

Alisertib DRUG

Alisertib enteric-coated tablets

Also known as: MLN8237

Alisertib 30 mg; Alisertib 40 mg

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (1)

National Cancer Centre

Tiong Bahru, 169610, Singapore

Location

Related Publications (1)

• 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.

  PMID: 26084989 DERIVED

MeSH Terms

Conditions

Lymphoma

Interventions

MLN 8237

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

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: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2012
• First Posted: January 19, 2012
• Study Start: February 6, 2012
• Primary Completion: October 8, 2013
• Study Completion: October 8, 2013
• Last Updated: March 15, 2019
• Results First Posted: March 15, 2019

Record last verified: 2018-11

Locations

SG (1)