A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Participants With Advanced Malignancies

Phase 1

Completed

Conditions: Advanced Malignancies

Interventions: Drug: alisertib

Registration Number: NCT00651664

Lead Sponsor: Millennium Pharmaceuticals, Inc.

Brief Summary: This is a multicenter, dose escalation, phase 1 study of MLN8237 in adult participants with advanced malignancies (excluding those with primary bone marrow involvement, such as leukemias and multiple myeloma).

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 59 patients. Participants were enrolled in one of 10 dose escalation arms:

* Alisertib 5 mg once daily (QD) for 7 Days (D)

* Alisertib 80 mg QD 7D

* Alisertib 150 mg QD 7D

* Alisertib 50 mg twice daily (BID) 7D

* Alisertib 60 mg BID 7D

* Alisertib 75 mg BID 7D

* Alisertib 100 mg BID 7D

* Alisertib 50 mg QD 14D

* Alisertib 50 mg QD 21D

* Alisertib 70 mg QD 21D

All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity.

This multi-center trial was conducted in Spain. The overall time to participate in this study was 730 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 59

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Alisertib 75 mg BID 7D	alisertib	Alisertib 75 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 8 cycles).
Alisertib 150 mg QD 7D	alisertib	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).
Alisertib 50 mg BID 7D	alisertib	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).
Alisertib 50 mg QD 21D	alisertib	Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg QD 21D	alisertib	Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Alisertib 100 mg BID 7D	alisertib	Alisertib 100 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 21 cycles).
Alisertib 50 mg QD 14D	alisertib	Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Alisertib 60 mg BID 7D	alisertib	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).
Alisertib 5 mg QD 7D	alisertib	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).
Alisertib 80 mg QD 7D	alisertib	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).

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Alisertib	Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)	The MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants.
Number of Participants With Dose-Limiting Toxicity (DLT)	First dose through 30 days following the last dose of study drug (up to 730 days)	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: 1. Grade 4 neutropenia lasting for ≥7 consecutive days during recovery 2. Grade 4 neutropenia with fever and/or infection 3. Confirmed platelet count \<25,000/mm\^3 4. ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis 5. ≥Grade 3 diarrhea that occurred despite therapy with loperamide 6. 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 7. Treatment delay of \>1 week because of a failure of adequate hematologic or nonhematologic recovery from the previous cycle of treatment. 8. Other alisertib-related nonhematologic toxicities ≥ Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.

Secondary Outcome Measures

Name	Time	Method
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing	Cycle1: 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
Peak/Trough Ratio for Aliserib 7 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
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
Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 or 8 (BID arms)
CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Tmax: Time of First Occurrence of Cmax for Alisertib 14 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 Days 7 and 14
Tmax: Time of First Occurrence of Cmax 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
Cmax: Maximum Observed Concentration for Alisertib 14 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 Days 7 and 14
Cmax: Maximum Observed Concentration for Alisertib 21 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 Days 14 and 21
Accumulation Ratio (Rac) for Alisertib 21 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21	Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1. Rac for Day 21=AUCt Day 21/AUCt Day 1.
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing	Cycle 1: Pre-dose (Baseline) and Day 7, 14 and 21, 6 hours post-dose	Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing	Cycle 1: Day 1, 6 hours post-dose; Days 7 6 and 24 hours post-dose; Day 21: 6 hours post-dose	Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing	Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose	Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing	Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose; Day 21: 6 hours post-dose	Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Accumulation Ratio (Rac) for Alisertib 7 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7	Rac for Day 7=AUCt Day 7/AUCt Day 1.
CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 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 Days 7 and 14
Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Accumulation Ratio (Rac) for Alisertib 14 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14	Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1.
Peak/Trough Ratio for Aliserib 14 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Peak/Trough Ratio for Aliserib 21 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Tmax: Time of First Occurrence of Cmax for Alisertib 21 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 Days 14 and 21
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing	Cycle 1: Pre-dose (Baseline) and Days 7 and 21, 6 hours post-dose	Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 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 Days 14 and 21
Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing	Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 21
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing	Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Day 7, 6 and 24 hours post-dose.	Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing	Cycle 1: Pre-dose (Baseline) and Day 1 and 7, 6 hours post-dose; Day 14, 6 and 24 hours post-dose	Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing	Cycle 1: Pre-dose (Baseline) and Days 1 and 7, 6 hours post-dose	Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing	Cycle 1: Pre-dose (Baseline) and Day 7, 6 hours post-dose	Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.