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

Study Overview
=================
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.

Official Title
-----------------
A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Patients With Advanced Malignancies

Conditions
-----------------
Advanced Malignancies

Intervention / Treatment
-----------------
* Drug: alisertib


Participation Criteria
=================
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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alisertib 5 mg QD 7D<br>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<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|
| Experimental: Alisertib 80 mg QD 7D<br>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<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|
| Experimental: Alisertib 150 mg QD 7D<br>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<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|
| Experimental: Alisertib 50 mg BID 7D<br>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<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|
| Experimental: Alisertib 60 mg BID 7D<br>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). | Drug: alisertib<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|
| Experimental: Alisertib 75 mg BID 7D<br>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). | Drug: alisertib<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|
| Experimental: Alisertib 100 mg BID 7D<br>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). | Drug: alisertib<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|
| Experimental: Alisertib 50 mg QD 14D<br>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). | Drug: alisertib<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|
| Experimental: Alisertib 50 mg QD 21D<br>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). | Drug: alisertib<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|
| Experimental: Alisertib 70 mg QD 21D<br>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). | Drug: alisertib<br>* Alisertib (MLN8237) capsules<br>* Other names: MLN8237;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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 Outcome Measures

| Outcome Measure | 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 |  | 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 | 
| 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 | 
| 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) | 
| Accumulation Ratio (Rac) for Alisertib 7 Day Dosing | Rac for Day 7=AUCt Day 7/AUCt Day 1. | Cycle 1: 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1. | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Accumulation Ratio (Rac) for Alisertib 21 Day Dosing | 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. | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21 | 
| 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 | 
| 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 | 
| Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | 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. | Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Day 7, 6 and 24 hours post-dose. | 
| Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing | 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. | Cycle 1: Pre-dose (Baseline) and Day 1 and 7, 6 hours post-dose; Day 14, 6 and 24 hours post-dose | 
| Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing | 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. | Cycle 1: Pre-dose (Baseline) and Day 7, 14 and 21, 6 hours post-dose | 
| Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | 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. | Cycle 1: Day 1, 6 hours post-dose; Days 7 6 and 24 hours post-dose; Day 21: 6 hours post-dose | 
| Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing | 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. | Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose | 
| Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing | 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. | 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 | 
| Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | 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. | Cycle 1: Pre-dose (Baseline) and Days 1 and 7, 6 hours post-dose | 
| Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing | 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. | Cycle 1: Pre-dose (Baseline) and Day 7, 6 hours post-dose | 
| Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing | 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. | Cycle 1: Pre-dose (Baseline) and Days 7 and 21, 6 hours post-dose |