Clinical trial NCT00500903: A Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Participants With Advanced Solid Tumors
Official title: An Open-Label, Dose Escalation Phase 1 Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Malignancies
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2007-07-13
Enrollment: 87
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: To determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of MLN8237 when given by mouth (PO) for a minimum of 7 and a maximum of 21 consecutive days, followed by a 14-day recovery period.

Detailed description: The drug tested in this study is called alisertib. Alisertib is being tested to treat people who have advanced malignancies. This study determined the dose-limiting toxicity, maximum tolerated dose, safety and pharmacokinetics (how the drug moves through the body) for alisertib when given once or twice a day for 7 to 21 days. This open label study enrolled 87 participants. Participants were enrolled in one of 3 treatment groups:

* Powder-in-Capsule (PIC) Dose Escalation (alisertib 5, 10, 20, 40, 80, 110 or 150 mg PIC , once daily (QD) for 7 days (D),or alisertib 25 mg, PIC, orally, QD 14D, or alisertib 25, 50 or 70 mg, PIC, orally, QD 21D, or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) 7D, alisertib 40 mg, PIC, orally, BID 14D
* ECT Dose Escalation (alisertib 10 or 20 mg, Enteric-coated Tablets (ECT), orally, QD for 7 to 21 days
* Relative Bioavailability (alisertib 40 mg ECT or PIC, orally, BID 7D in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, BID 7D in cycle 2, followed by alisertib 50 mg PIC orally, BID 7D in each additional All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity. This multi-center trial was conducted in the United States. The overall time to participate in this study was 1011 days. Participants made multiple visits to the clinic, including a final visit 30 days after receiving their last dose of alisertib for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed metastatic and/or advanced solid tumors (including lymphomas) for which no effective standard treatment is available
* Aged 18 years or more
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Expected survival longer than 3 months from enrollment in the study
* Radiographically or clinically evaluable tumor; however, measurable disease as defined by (RECIST) criteria is not required for participation in this study
* Suitable venous access for the conduct of blood sampling for MLN8237 PK
* Recovered from the reversible effects of prior antineoplastic therapy (with the exception of alopecia and grade 1 neuropathy) with at least 4 weeks elapsed since the last exposure to cytotoxic chemotherapy or to radiotherapy and at least 6 weeks elapsed since exposure to nitrosoureas or mitomycin C. Participants treated with fully human monoclonal antibodies must not have received treatment with such antibodies for at least 6 weeks, and those treated with chimeric monoclonal antibodies must not have received treatment with such antibodies for at least 4 weeks. Participants treated with noncytotoxic small molecule drugs (eg, tyrosine kinase inhibitors, such as Tarceva®, and hormonal agents, such as Femara®) must not have received treatment with these drugs for at least 2 weeks before the first dose of MLN8237 is given.
* Male participants must use an appropriate method of barrier contraception (eg, condoms) and inform any sexual partners that they must also use a reliable method of contraception (eg, birth control pills) from the time of informed consent until 3 months after the last dose of study treatment.
* Female participants must be postmenopausal, surgically sterilized, or willing to use reliable methods of birth control (eg, a hormonal contraceptive, an intrauterine device, diaphragm with spermicide, or abstinence) and inform male sexual partners that they must also use a reliable method of contraception (eg, condoms) from the time of informed consent until 3 months after the last dose of study treatment.
* Willing and able to give written informed consent before the conduct of any study related procedure that is not part of normal medical care, and willing to comply with the protocol

Exclusion Criteria:

* Pregnant or lactating
* Major surgery or serious infection within the 28 days preceding the first dose of study treatment
* Life-threatening illness or uncontrolled medical illness unrelated to cancer
* Ongoing nausea or vomiting of any severity
* \> Grade 1 diarrhea
* Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN8237. Examples include but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease.
* History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.
* Difficulty swallowing capsules
* Inability to take nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of MLN8237
* Received more than 4 previous cytotoxic chemotherapeutic regimens including regimens used as adjuvant or neo-adjuvant therapies. There is no limit on the number of noncytotoxic therapies (eg, hormonal and immunologic) that participants may have received. Tyrosine kinase inhibitors (eg, Tarceva and Iressa®) are considered noncytotoxic compounds.
* Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution
* Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow
* Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system (CNS) metastasis but who have no radiographic or clinical evidence of residual tumor (eg, following complete surgical resection or stereotactic radiosurgery) are not excluded from participation in this study
* Absolute neutrophil count \<1500/mm\^3; platelet count \<100,000/mm\^3
* Serum creatinine \>1.6 mg/dl or a measured or estimated creatinine clearance \<40 mL/minute
* Bilirubin \>1.5 times the upper limit of the normal range (ULN); aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>2.5 times the ULN, and alkaline phosphatase (ALP) \>2.5 times the ULN. Both the AST and ALP may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of metastatic disease to liver and/or to bone; however, the ALT must in all circumstances be \<2.5 times the ULN
* Abnormalities on 12-lead electrocardiogram (ECG) considered by the investigator to be clinically significant or baseline prolongation of the rate-corrected QT interval (eg, repeated demonstration of QTc interval \> 450 milliseconds)
* Left ventricular ejection fraction (LVEF) \< 50%
* Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Testing for these agents is not required in the absence of clinical findings or suspicion.
* Less than 4 weeks between the last dose of an investigational agent and the first dose of MLN8237
* Admission or evidence of benzodiazepine dependence or abuse and/or alcohol abuse or an inability to restrict consumption of alcohol to no more than 1 standard unit of alcohol per day during the study and for 30 days from the last dose of study treatment. A standard unit of alcohol is defined as one 12-oz (150mL) beer, 1.5 oz (45mL) of 80-proof alcohol, or one 6-oz (175mL) glass of wine.
* Lactose intolerant, for the food effect cohort only.

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicity (DLT)
timeFrame: Cycle 1 Day 1 up to Day 35 (alisertib daily for 7 to 21 days followed by a 14-day recovery period)
measure: Maximum Tolerated Dose (MTD) of Alisertib
timeFrame: From first dose of study drug to 30 days after the last dose (up to 1011 days)
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug to 30 days after the last dose (up to 1011 days)
Secondary outcomes:
measure: Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
timeFrame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
timeFrame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
timeFrame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
timeFrame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
measure: CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: AUCt: Area Under the Concentration--Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Terminal Half-Life for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
timeFrame: Cycle 1 Day 14 predose and at multiple time-points (up to 10 hours) postdose
measure: Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
timeFrame: Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose
measure: Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
timeFrame: Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose
measure: CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
timeFrame: Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose
measure: Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
measure: CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose
measure: Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose
measure: AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose
measure: Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
timeFrame: Cycle 1 Day 21 predose and at multiple time points (up to 10 hours) postdose
measure: Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
timeFrame: Cycle 1 Days 14 and 21 predose and at multiple timepoints (up to 10 hours) postdose
measure: Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
timeFrame: Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose
measure: CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
timeFrame: Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose
measure: Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose
measure: CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Cycle 1 Day 8
measure: Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
measure: CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
measure: Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing
timeFrame: Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing
timeFrame: Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose
measure: AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing
timeFrame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
measure: AUCt: Area Under the Concentration-time Curve From Time 0 to Time t as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7
timeFrame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Cmax: Maximum Observed Concentration as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7
timeFrame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing
timeFrame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing
timeFrame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 14 Days (QD14D) Dosing
timeFrame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 14 Days (QD14D) Dosing
timeFrame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing
timeFrame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing
timeFrame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing
timeFrame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing
timeFrame: Baseline and Cycle 1 Day 7, 6 hours postdose
measure: Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing
timeFrame: Baseline and Cycle 1 Day 7, 6 hours postdose
measure: Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1
timeFrame: Cycle 1 Day 1 predose
measure: Best Overall Response Based on Investigator Assessment
timeFrame: Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months)
measure: Duration Of Response (DOR)
timeFrame: Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months)
measure: Effect of Food on the Pharmacokinetics (PK) of Alisertib
timeFrame: Up to 6 months
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Sarah Cannon Research Institute (SCRI)
state: Tennessee
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References: