Clinical trial NCT01844583: Safety, Tolerability and Pharmacokinetic (PK) of Concomitant Esomeprazole and Rifampin, and QT Study on Single and Multiple-doses of Alisertib
Official title: Study of the Effect of Esomeprazole or Rifampin on the Pharmacokinetics of Alisertib and Evaluation of the Effect of Alisertib on the QTc Interval in Patients With Advanced Solid Tumors or Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Lymphoma
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2013-05-01
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the drug-drug interaction (DDI) of either esomeprazole or rifampin on the single-dose PK of alisertib, and to complete an intensive QT study of single and multiple-dose alisertib.

Detailed description: The drug tested in this study is called alisertib. Alisertib is being tested to assess the effect of a proton pump inhibitor and strong metabolic inducer on the PK of a single 50 mg dose of alisertib administered as enteric-coated tablets (ECTs).

The study enrolled 55 patients. Participants received either:

* Esomeprazole 40 mg and Alisertib 50 mg
* Rifampin 600 mg and Alisertib 50 mg

All participants were asked to take one tablet of alisertib either once or twice daily in all cycles. In Cycle 2, participants were asked to take alisertib plus either esomeprazole or rifampin.

This trial was conducted the United States. The overall time to participate in this study was 10 months. Participants made multiple visits to the clinic plus a final visit, 30 days after receiving their last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

* Male or female participants 18 years or older
* Histologically or cytologically confirmed metastatic and/or advanced solid tumors or lymphomas
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Expected survival longer than 3 months from enrollment in the study
* Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse
* Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse

Exclusion Criteria:

* Treatment with any anticancer therapy or any investigational agents within 4 weeks before the first dose of alisertib

  - Known hypersensitivity or intolerance to rifampin (for participants considered for the rifampin drug-drug interaction \[DDI\] group) or to esomeprazole (for participants considered for the esomeprazole DDI group)
* Recurrent nausea and/or vomiting within 14 days before the first dose of alisertib, and known gastrointestinal (GI) abnormality or GI procedure that could interfere with or modify the oral absorption or tolerance of alisertib
* Participants requiring treatment with clinically significant enzyme inducers within 14 days before the first dose of alisertib and/or requiring the use of these medications during the study
* A medical condition requiring use of pancreatic enzymes; or daily, chronic, or regular use of proton pump inhibitors (PPI); or histamine (H2) receptor antagonists
* Participants requiring systemic anticoagulation (excluding low-dose aspirin, or low-dose anticoagulation to maintain patency of venous access devices).
* Any cardiovascular condition
* Female participants who are lactating or have a positive serum pregnancy test
* Major surgery within the 14 days preceding the first dose of alisertib

  - Life-threatening or uncontrolled medical illness unrelated to cancer
* Newly diagnosed or uncontrolled cancer-related central nervous system (CNS) disease
* Autologous stem cell transplant within 3 months
* Prior allogeneic bone marrow or other organ transplantation

  - Other severe acute or chronic medical or psychiatric condition
* Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection

Please note there are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.

Primary outcomes:
measure: Cmax: Maximum Observed Concentration for Alisertib in Presence and Absence of Esomeprazole
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm
measure: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Presence and Absence of Esomeprazole
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm
measure: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alisertib in Presence and Absence of Esomeprazole
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib in Presence and Absence of Esomeprazole
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm
measure: Terminal Phase Elimination Half-life (T1/2) for Alisertib in Presence and Absence of Esomeprazole
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm
measure: Cmax: Maximum Observed Concentration for Alisertib in Presence and Absence of Rifampin
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm
measure: AUC(Last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Presence and Absence of Rifampin
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm
measure: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alisertib in Presence or Absence of Rifampin
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib in Presence and Absence of Rifampin
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm
measure: Phase Elimination Half-life (T1/2) for Alisertib in Presence and Absence of Rifampin
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm
measure: Change From the Time-matched Baseline in the Individually Corrected QTc Interval (QTcI)
timeFrame: Baseline, Days 1 and 10 multiple timepoints postdose (up to 24 hours) in Cycle 1
Secondary outcomes:
measure: Change From the Time-matched Baseline in the Fridericia Correction of QTc (QTcF)
timeFrame: Baseline, Days 1 and 10 multiple timepoints postdose (up to 24 hours) in Cycle 1
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From the first dose through 30 days after administration of the last dose of study drug (up to 328 days)
Other outcomes:
Locations:
city: Sarasota
country: United States
state: Florida
city: Saint Louis
country: United States
state: Missouri
city: Oklahoma City
country: United States
state: Oklahoma
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Madison
country: United States
state: Wisconsin
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References: