A Phase I Clinical and Pharmacodynamic Study of MLN8237,... | NCT00651664

NCT00651664

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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Document Section

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Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
2006-006048-68	EudraCT Number
U1111-1187-1151	Registry Identifier	WHO

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Alisertib 5 mg QD 7D	Experimental	Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).	Drug: alisertib
Alisertib 80 mg QD 7D	Experimental	Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Drug: alisertib
Alisertib 150 mg QD 7D	Experimental	Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Drug: alisertib
Alisertib 50 mg BID 7D	Experimental	Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).	Drug: alisertib
Alisertib 60 mg BID 7D	Experimental	Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).

Name	Type	Description	Arm Group Labels	Other Names
alisertib	Drug	Alisertib (MLN8237) capsules	Alisertib 100 mg BID 7D Alisertib 150 mg QD 7D Alisertib 5 mg QD 7D Alisertib 50 mg BID 7D

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Dose-Limiting Toxicity (DLT)	DLT was evaluated using the National Cancer Institutes Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0; defined as any of the following events related to alisertib therapy: Grade 4 neutropenia lasting for ≥7 consecutive days during recovery Grade 4 neutropenia with fever and/or infection Confirmed platelet count <25,000/mm^3 ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis ≥Grade 3 diarrhea that occurred despite therapy with loperamide Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (< 1 week) Grade 3 fatigue Treatment delay of >1 week because of a failure of adequate hematologic or nonhematologic recovery from the previous cycle of treatment. Other alisertib-related nonhematologic toxicities ≥ Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.	First dose through 30 days following the last dose of study drug (up to 730 days)
Maximum Tolerated Dose (MTD) of Alisertib	The MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants.	Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)

Secondary Outcomes

Measure	Description	Time Frame
Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing		Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7
Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing

Other Outcomes

Measure	Description	Time Frame
Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1	A blood sample was collected prior to alisertib dosing for the purpose of genotyping for polymorphisms in UGT1A1. The percentage of participants in the polymorphism categories: wt/wt, wt/28, 28/28, 28/wt, 28/other and other/other is reported. wt=wild type. 28 polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Have a histologically or cytologically confirmed metastatic and/or advanced malignancy (including lymphomas but excluding malignancies with extensive bone marrow involvement such as leukemias and multiple myeloma) for which standard treatment does not offer curative or life-prolonging potential.
Aged 18 years or more.
Eastern Cooperative Oncology Group performance status 0 or 1.
Have an expected survival longer than 3 months from enrollment in the study.
Radiographically or clinically evaluable tumor.
Suitable venous access for the conduct of blood sampling.
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® [erlotinib], and hormonal agents, such as Femara® [letrozole]) must not have received treatment with these drugs for at least 2 weeks before the first dose of alisertib was given.
Male participants must use an appropriate method of barrier contraception and inform any sexual partners that they must also use a reliable method of contraception from the time of informed consent until 3 months after the last dose of study treatment.
Female participants must be postmenopausal at least 1 year, OR surgically sterile, OR if of childbearing potential, agree to 2 effective methods of nonhormonal contraception, or agree to completely abstain from heterosexual intercourse.
Able to give written consent.

Exclusion Criteria:

Pregnant or lactating.
Major surgery or serious infection within the 28 days preceding the first dose of study treatment.
Life-threatening or uncontrolled medical illness unrelated to cancer.
Ongoing nausea or vomiting of any severity.
>Grade 1 diarrhea. Participants who require ongoing therapy with an antimotility agent to control diarrhea to a Grade 1 or lower level are not allowed to participate in this trial.
Known gastrointestinal disease or gastrointestinal procedures that could interfere with the oral absorption or tolerance of MLN8237.
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 (in participants with metastatic breast cancer, a total of 5 previous cytotoxic chemotherapeutic regimens is permitted).
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 for the distribution of active bone marrow in adults).
Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system 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(ANC) < 1500/mm^3; platelet count< 100,000/mm^3.
Serum creatinine >1.6 mg/dL or a measured or estimated (Cockcroft-Gault formula) creatinine clearance <40 mL/min
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 could be elevated up to 5 times the ULN if their elevation could be reasonably ascribed to the presence of metastatic disease to liver and/or to bone; however, the ALT in all circumstances must have been <2.5 times the ULN.
Abnormalities on 12-lead electrocardiogram 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).
Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C.
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.
Activated partial thromboplastin time (aPTT) and/or prothrombin time (PT) exceeding the upper limit of the normal range.
Known bleeding diathesis or history of abnormal bleeding.
Ongoing therapy with an anticoagulant (e.g., aspirin, plavix, coumadin).

Name	Affiliation	Role
Medical Director Clinical Science	Takeda	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Ciutat Sanitaria Vall d'Hebron - Servicio de Oncologia		Barcelona		08035	Spain
H. Clínico Universitario de Valencia

Arm/Group Information

ID	Title	Description
FG000	Alisertib 5 mg QD 7D	Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
FG001	Alisertib 80 mg QD 7D	Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
FG002	Alisertib 150 mg QD 7D	Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
FG003	Alisertib 50 mg BID 7D	Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
FG004	Alisertib 60 mg BID 7D	Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
FG005	Alisertib 75 mg BID 7D	Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
FG006	Alisertib 100 mg BID 7D	Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
FG007	Alisertib 50 mg QD 14D	Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
FG008	Alisertib 50 mg QD 21D	Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
FG009	Alisertib 70 mg QD 21D	Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).

ID	Title	Description
BG000	Alisertib 5 mg QD 7D	Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
BG001	Alisertib 80 mg QD 7D

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	Number of Participants With Dose-Limiting Toxicity (DLT)	DLT was evaluated using the National Cancer Institutes Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0; defined as any of the following events related to alisertib therapy: Grade 4 neutropenia lasting for ≥7 consecutive days during recovery Grade 4 neutropenia with fever and/or infection Confirmed platelet count <25,000/mm^3 ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis ≥Grade 3 diarrhea that occurred despite therapy with loperamide Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (< 1 week) Grade 3 fatigue Treatment delay of >1 week because of a failure of adequate hematologic or nonhematologic recovery from the previous cycle of treatment. Other alisertib-related nonhematologic toxicities ≥ Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.	DLT Evaluable Population was defined as all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.	Posted		Number		participants		First dose through 30 days following the last dose of study drug (up to 730 days)

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Alisertib 5 mg QD 7D	Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).